Vitamin B12 deficiency

Vitamin B12 deficiency also known as cobalamin deficiency is characterized by megaloblastic anemia, fatigue, weakness, constipation, loss of appetite, and weight loss ¹, ², ³. Neurological changes, such as numbness and tingling in the hands and feet, can also occur ⁴, ⁵. Additional symptoms of vitamin B-12 deficiency include difficulty maintaining balance, depression, confusion, dementia, poor memory, and soreness of the mouth or tongue ⁶. The neurological symptoms of vitamin B12 deficiency can occur without anemia, so early diagnosis and intervention is important to avoid irreversible damage ⁷. During infancy, signs of a vitamin B12 deficiency include failure to thrive, movement disorders, developmental delays, and megaloblastic anemia ⁸. Many of these symptoms are general and can result from a variety of medical conditions other than vitamin B-12 deficiency.

In healthy adults, vitamin B12 deficiency is uncommon, mainly because your body stores 1,000 to 2,000 times as much vitamin B12 (about 3 to 5 mg vitamin B12) as you’d typically eat in a day – total body stores can exceed 2,500 micrograms (2,500 μg), daily turnover is slow, and dietary intake of only 2.4 mcg/day (2.4 μg/day) is sufficient to maintain adequate vitamin B12 status (see Recommended Dietary Allowance [RDA]) ⁹. Therefore, when there is little or no vitamin B12 in your diet, vitamin B12 stores (about 3 to 5 mg) may last for up to 5–10 years before the signs and symptoms of vitamin B12 deficiency are seen clinically ⁹. In elderly individuals, vitamin B12 deficiency is more common mainly because of impaired intestinal absorption that can result in marginal to severe vitamin B12 deficiency in this population. The Recommended Dietary Allowance (RDA) for vitamin B12 is 2.4 micrograms per day (2.4 μg/day) for adolescents and adults. It is slightly higher for women who are pregnant (2.6 mcg/day) or breastfeeding (2.8 mcg/day). Currently, to maintain a healthy hematological status and serum vitamin B12 levels, average daily intakes of vitamin B12 from food of 5.94 mcg for men and 3.78 mcg for women aged 20 and older have been recommended ¹⁰. For children aged 2–19 years old, mean daily intakes of vitamin B12 from food range from 3.76 mcg to 4.55 mcg ¹¹. The original estimates of dietary folate and vitamin B12 requirements and recommended dietary allowances (RDAs) were based on the amount needed to avoid manifest deficiency disorders (megaloblastic anemia, with sub-acute combined degeneration of the cord in the case of vitamin B12 deficiency) and on levels observed in populations. However, these levels do not essentially represent necessary requirements ¹⁰.

The signs and symptoms of vitamin B12 deficiency can take several years to appear ¹², ¹³. The signs and symptoms of vitamin B12 deficiency can include the hallmark megaloblastic anemia (characterized by large, abnormally nucleated red blood cells) as well as low counts of white and red blood cells, platelets, or a combination; glossitis of the tongue (a condition in which your tongue becomes inflamed and swollen) (Figure 3); fatigue; palpitations; pale skin; dementia; weight loss; and infertility ¹⁴, ¹⁵, ¹³. Neurological changes, such as numbness and tingling in the hands and feet, can also occur ¹³. These neurological symptoms can occur without anemia, so early diagnosis and intervention is important to avoid irreversible damage ¹⁶. In addition, some studies have found associations between vitamin B12 deficiency or low vitamin B12 intakes and depression ¹⁷, ¹⁸, ¹⁹. In pregnant and breastfeeding women, vitamin B12 deficiency might cause neural tube defects, developmental delays, failure to thrive, and anemia in babies ¹³.

Vitamin B12 deficiency with the classic hematologic and neurologic signs and symptoms is uncommon ²⁰. However, low or marginal vitamin B12 status (200–300 pg/mL [148–221 pmol/L]) without these symptoms is much more common, at up to 40% in Western populations, especially in those with low intakes of vitamin B12-rich foods ²¹, ²⁰. The prevalence of vitamin B12 deficiency varies by cutoff level and biomarker used. For example, among adults aged 19 and older who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004, the rate of low vitamin B12 levels in serum was 3% with a cutoff of less than 200 pg/mL (148 pmol/L) and 26% with a cutoff of less than 350 pg/mL (258 pmol/L) ²². Approximately 21% of adults older than 60 had abnormal levels of at least one vitamin B12 biomarker ²².

The most common cause of vitamin B12 deficiency is autoimmune pernicious anemia, a condition that carries an increased risk of gastric cancer. In pernicious anemia, absorption is impaired due to intrinsic factor deficiency arising from autoimmune destruction of parietal cells ²³. Other common causes of vitamin B12 deficiency include gastrectomy, ileal resection, pancreatic insufficiency, and malabsorption syndromes including Crohn’s disease and celiac disease. Other less common causes of vitamin B12 deficiency include use of medications such as biguanides (metformin), antacids (proton pump inhibitors and H2 receptors antagonists), aminoglycoside, antibiotics and colchicines, and rarely, malabsorption due to gastrointestinal bacterial overgrowth, congenital defects (e.g. birth transcobalamin deficiency), and infestation ¹³. Pure nutritional deficiency is rare and usually occurs only in strict vegans ²⁴. Because people who have difficulty absorbing vitamin B12 from food absorb free vitamin B12 normally, their vitamin B12 deficiency tends to be less severe than that of individuals with pernicious anemia, who cannot absorb either food-bound or free vitamin B12. It is recommended that vegetarians and vegans take vitamin B12 supplements to prevent vitamin B12 deficiency ²⁵. Certain congenital conditions, such as hereditary intrinsic factor defects and congenital vitamin B12 malabsorption (Imerslund-Gräsbeck disease), can also cause severe vitamin B12 deficiency ¹⁵. In some cases, vitamin B12 deficiency can be a risk factor for cardiovascular disease ²⁶.

In the United States and the United Kingdom, the prevalence of vitamin B12 deficiency is approximately 6% in persons younger than 60 years, and nearly 20% in those older than 60 years ²⁷, ²⁸. Latin American countries have a clinical or subclinical B12 deficiency rate of approximately 40% ¹². The prevalence is 70% in Kenyan school children, 80% in East Indian preschool-aged children, and 70% in East Indian adults ¹². Pawlak ²⁹ examined the prevalence of vitamin B12 deficiency among individuals adhering to vegetarian diets. The reviewed studies show relatively high vitamin B12 deficiency prevalence among vegetarians. Vitamin B12 deficiency in infants is about 45%, among the children and adolescents ranging from 0% to 33.3%, and among pregnant women ranging from 17% to 39%, dependent on the trimester ²⁹. Adults and elderly individuals had a deficiency range of 0 to 86.5% ²⁹. Higher vitamin B12 deficiency prevalence was reported in vegans than in other vegetarians, while B12 deficiency prevalence of 0% was reported among vegans who consumed vitamin B12-fortified foods, highlighting that vitamin B12 supplements to ensure adequate vitamin B12 intake should be considered in these individuals ¹⁰.

Certain risk factors increase the prevalence of vitamin B12 deficiency (see Table 1) ³⁰. Dietary insufficiency, pernicious anemia (i.e., an autoimmune process that reduces available intrinsic factor and subsequent absorption of vitamin B12) ¹² and long-term use of metformin or stomach acid-suppressing medications have been implicated in B12 deficiency ³¹, ³². A multicenter randomized controlled trial of 390 patients with diabetes mellitus showed that those taking 850 mg of metformin three times per day had an increased risk of vitamin B12 deficiency (number needed to harm = 14 per 4.3 years) and low vitamin B12 levels (number needed to harm = 9 per 4.3 years) vs. placebo ³¹. This effect increased with duration of metformin therapy, and patients had an unclear prophylactic supplementation response ³¹. A case-control study that compared 25,956 patients who had vitamin B12 deficiency with 184,199 control patients found a significantly increased risk of vitamin B12 deficiency in patients who had taken proton pump inhibitors or histamine H2 blockers for at least two years ³². In light of these findings, long-term use of these medications should be periodically reassessed, particularly in patients with other risk factors for vitamin B12 deficiency ³¹, ³².

Screening persons at average risk of vitamin B12 deficiency is not recommended ¹³. Screening for vitamin B12 deficiency should be considered in patients with risk factors, and diagnostic testing for vitamin B12 deficiency should be considered in those with suspected clinical signs and symptoms of vitamin B12 deficiency ³³, ¹², ³⁴.

The recommended laboratory evaluation for patients with suspected vitamin B12 deficiency includes a complete blood count (CBC) and serum vitamin B12 level ³³, ³⁵. A level of less than 150 pg per mL (111 pmol per L) is diagnostic for deficiency ³³, ¹². Serum vitamin B12 levels may be artificially elevated in patients with alcoholism, liver disease, or cancer because of decreased liver clearance of transport proteins and resultant higher circulating levels of vitamin B12; physicians should use caution when interpreting laboratory results in these patients ³⁶, ³⁷. In patients with a normal or low-normal serum vitamin B12 level, complete blood count results demonstrating macrocytosis, or suspected clinical manifestations, a serum methylmalonic acid (MMA) level is an appropriate next step ³⁸ and is a more direct measure of vitamin B12’s physiologic activity ³³, ¹². Although not clinically validated or available for widespread use, measurement of holotranscobalamin, the metabolically active form of vitamin B12, is an emerging method of detecting deficiency ¹³.

Typically, vitamin B12 deficiency is treated with intramuscular injections of cyanocobalamin or hydroxocobalamin, because this method bypasses any barriers to absorption. Hydroxocobalamin is usually the recommended option as it stays in the body for longer. Approximately 10% of the standard injectable dose of 1 mg is absorbed, which allows for rapid replacement in patients with severe deficiency or severe neurologic symptoms ¹⁵. Guidelines from the British Society for Haematology recommend injections three times per week for two weeks in patients without neurologic deficits ³⁸. If neurologic deficits are present, injections should be given every other day for up to three weeks or until no further improvement is noted.

However, high doses of oral vitamin B12 might also be effective ³⁹. A 2018 Cochrane review included three randomized controlled trials (RCTs) that compared very high doses (1,000–2,000 mcg) of oral with intramuscular vitamin B12 for vitamin B12 deficiency in a total of 153 participants ²³. The evidence from these studies, although of low quality, showed that the ability of high oral doses of vitamin B12 supplements to normalize serum vitamin B12 was similar to that of intramuscular vitamin B12. The British Society for Haematology recommends intramuscular vitamin B12 for severe deficiency and malabsorption syndromes, whereas oral replacement may be considered for patients with asymptomatic, mild disease with no absorption or compliance concerns ³⁸.

If vitamin B12 deficiency coexists with folate deficiency, vitamin B12 should be replaced first to prevent subacute combined degeneration of the spinal cord ¹².

The British Society for Haematology does not recommend retesting vitamin B12 levels after treatment has been initiated, and no guidelines address the optimal interval for screening high-risk patients ³⁸. In general, patients with an irreversible cause should be treated indefinitely, whereas those with a reversible cause should be treated until the deficiency is corrected and symptoms resolve ¹².

Figure 1. Vitamin B12 absorption and transport

Figure 2. Vitamin B12 deficiency pathophysiology

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Figure 3. Glossitis secondary to vitamin B12 deficiency anemia

Footnotes: (A) Generalized dryness of the tongue of a 61-year-old woman with vitamin B12 deficiency, with atrophy (blue arrowheads) and erythematous plaques (white arrowheads). (B) Normal appearance of the tongue 3 days after the patient received a single injection of vitamin B12.

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Table 1. Risk factors for vitamin B12 deficiency

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Table 2. Clinical and laboratory findings in vitamin B12 deficiency

General symptoms	Weight loss observed in most patients
General symptoms	Low-grade fever occurs in one third of newly diagnosed patients and promptly disappears with treatment
Gastrointestinal symptoms	Smooth tongue (50% of patients) with loss of papillae. Changes in taste and loss of appetite
	Patients may report either constipation or having several semi-solid bowel movements daily
	Anorexia, nausea, vomiting, heartburn, pyrosis, flatulence and a sense of fullness
Brain	Altered mental status. Cognitive defects (“megaloblastic madness”): depression, mania, irritability, paranoia, delusions, lability
Sensory organs	Optic atrophy, anosmia, loss of taste, glossitis
Bone marrow	Hypercellular bone marrow
	Increased erythroid precursors
	Open, immature nuclear chromatin
	Dyssynchrony between maturation of cytoplasm and nuclei
	Giant bands, metamyelocytes
	Karyorrhexis, dysplasia
	Abnormal results on flow cytometry and cytogenetic analysis
Spinal cord	Myelopathy
	Spongy degeneration
	Paresthesias
	Loss of proprioception: vibration, position, ataxic gait, limb weakness/spasticity (hyperreflexia)
	Positive Romberg sign
	Lhermitte’s sign
	Segmental cutaneous sensory level
Autonomic nervous system	Postural hypotension
	Incontinence
	Impotence
Peripheral nervous system	Cutaneous sensory loss
	Hyporeflexia symmetric weakness
	Paresthesias
Genitourinary symptoms	Urinary retention and impaired micturition may occur because of spinal cord damage. This can predispose patients to urinary tract infections
Reproductive system	Infertility
Abnormalities in infants and children	Developmental delay or regression, permanent disability
	The patient does not smile
	Feeding difficulties
	Hypotonia, lethargy, coma
	Hyperirritability, convulsions, tremors, myoclonus
	Microcephaly
	Choreoathetoid movements, peripheral blood
	Macrocytic red cells, macro-ovalocytes
	Anisocytosis, fragmented forms
	Hypersegmented neutrophils
	Leukopenia, possible immature white cells
	Thrombocytopenia
	Pancytopenia
	Elevated lactate dehydrogenase level (extremes possible)
	Elevated indirect bilirubin and aspartate aminotransferase levels
	Decreased haptoglobin level
	Elevated levels of methylmalonic acid, homocysteine, or both

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Folic Acid and Vitamin B12 Deficiency

Large amounts of folic acid can mask the damaging effects of Vitamin B-12 deficiency by correcting the megaloblastic anemia caused by Vitamin B-12 deficiency ², ⁴ without correcting the neurological damage that also occurs ¹, ⁴³. Moreover, preliminary evidence suggests that high serum folate levels might not only mask Vitamin B-12 deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with Vitamin B-12 deficiency ⁴⁴, ⁴⁵. Permanent nerve damage can occur if Vitamin B-12 deficiency is not treated. For these reasons, folic acid intake from fortified food and supplements should not exceed 1,000 mcg daily in healthy adults ⁴.

What is vitamin B12?

Vitamin B12 is also known as cobalamin or cyanocobalamin (man-made form of vitamin B12), is a nutrient that helps keep your body’s nerve and blood cells healthy and helps make DNA, the genetic material in all cells. Vitamin B-12 is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement and a prescription medication. Vitamin B12 has the largest and most complex chemical structure of all the vitamins. Vitamin B12 is unique among vitamins in that it contains a metal ion, cobalt ⁴⁶, ¹, ⁴⁷, ², ⁴⁸. For this reason cobalamin is the term used to refer to compounds having vitamin B12 activity ⁴⁶. Methylcobalamin and adenosylcobalamin (5-deoxyadenosylcobalamin) are the two forms of “active” vitamin B12 used by your body ⁴⁹, ⁵⁰, ⁵¹. The form of cobalamin used in most nutritional supplements and fortified foods, cyanocobalamin (man-made form of vitamin B12), is readily converted to adenosylcobalamin (5-deoxyadenosylcobalamin) and methylcobalamin in your body. In mammals, vitamin B-12 is a cofactor for only two enzymes, methionine synthase and L-methylmalonyl-coenzyme A mutase ⁵², ⁵³. Methionine synthase catalyzes the conversion of homocysteine to methionine ⁵¹, ⁷. Methionine is required for the formation of S-adenosylmethionine, a universal methyl donor for almost 100 different substrates, including DNA, RNA, hormones, proteins, and lipids. L-methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to succinyl-CoA in the degradation of propionate ², ⁵¹, ⁷, an essential biochemical reaction in fat and protein metabolism. Succinyl-CoA is also required for hemoglobin synthesis.

Vitamin B12 is required for the development, myelination, and function of the central nervous system; healthy red blood cell formation; and DNA synthesis ¹, ⁴⁷, ², ⁴⁸, ⁵¹.

Large amounts of Vitamin B-12 seem to be nontoxic but are not recommended for regular use (ie, as a general tonic). The Recommended Dietary Allowance (RDA) for vitamin B12 is 2.4 micrograms per day (μg/day) for adolescents and adults. It is slightly higher for women who are pregnant (2.6 mcg/day) or breastfeeding (2.8 mcg/day) ⁴⁶. The Food and Nutrition Board at the National Academies of Sciences, Engineering, and Medicine did not establish a Tolerable Upper Intake Level (maximum daily intake unlikely to cause adverse health effects) for vitamin B12 because of its low potential for toxicity ⁵¹. Even at large doses, vitamin B12 is generally considered to be safe because your body does not store excess amounts ³⁹.

Vitamin B-12 also helps prevent a type of anemia called megaloblastic anemia that makes people tired and weak. Your body cannot make vitamin B12. Vitamin B-12 is synthesized only by bacteria. While present in animal products, including meats, fish, shellfish, dairy products, and eggs, it is absent in plant-based foods. People most at risk for vitamin B12 deficiency are vegans, as diets devoid of animal products will result in B12 deficiency. However, vitamin B12 issues can be caused by taking some types of stomach acid blockers. Also, some people have an autoimmune or inflammatory condition of the stomach wall that degrade the proteins that aid vitamin B12 absorption.

Two steps are required for your body to absorb Vitamin B-12 from food.

First, food-bound Vitamin B-12 is released in the stomach’s acid environment (hydrochloric acid and and gastric protease in the stomach separate Vitamin B-12 from the protein to which Vitamin B-12 is attached in food) and is bound to R protein (haptocorrin) ⁵¹. Approximately 1.2% of vitamin B12 is absorbed passively without the help of intrinsic factor (IF) ⁵⁴. When synthetic Vitamin B-12 is added to fortified foods and dietary supplements, it is already in free form and thus, does not require this separation step. If a patient receives the oral formulation of cobalamin at high doses, this passive absorption is sufficient to replenish vitamin B12 deficiency (a lack of vitamin B12). If intrinsic factor (IF) is present in an adequate amount, then oral cobalamin is absorbed with the help of intrinsic factor (IF). When administering cobalamin parenterally, it bypasses the intestinal barrier, absorbs quickly by diffusion, and enters into the systemic circulation ²³.
Second, pancreatic enzymes cleave this B12 complex (B12-R protein) in the small intestine. After cleavage, intrinsic factor (IF), a protein secreted by parietal cells situated in the mucosa of your stomach, binds with the free Vitamin B-12. Intrinsic factor is required for absorption of Vitamin B-12, which takes place in the terminal ileum ⁵¹, ⁵⁵. Intrinsic factor (IF) binds to vitamin B12 and the complex is transported across the cell membrane bound to another glycoprotein called transcobalamin ²³. Approximately 56% of a 1 mcg oral dose of Vitamin B-12 is absorbed, but absorption decreases drastically when the capacity of intrinsic factor is exceeded (at 1–2 mcg of Vitamin B-12) ⁹. Some people have pernicious anemia, a condition where they cannot make intrinsic factor (IF). As a result, they have trouble absorbing Vitamin B-12 from all foods and dietary supplements.

Pernicious anemia is an autoimmune disease that affects the gastric mucosa and results in gastric atrophy. This leads to the destruction of parietal cells, achlorhydria, and failure to produce intrinsic factor, resulting in Vitamin B-12 malabsorption ², ⁵¹, ⁵⁶, ⁵⁷, ⁵⁸. If pernicious anemia is left untreated, it causes vitamin B-12 deficiency (a lack of vitamin B12), leading to megaloblastic anemia and neurological disorders, even in the presence of adequate dietary intake of vitamin B-12. Pernicious anemia can cause fatigue, weakness, constipation, loss of appetite, and weight loss. Numbness and tingling in the hands and feet, depression, confusion, or poor memory can also occur. Symptoms of vitamin B12 deficiency can take decades to develop, and can usually only be diagnosed by a medical professional. For more details see below – Groups at Risk of Vitamin B12 deficiency.

In the blood plasma, Vitamin B-12 is bound to transcobalamins 1 and 2 ⁵⁹. Transcobalamin 2 is responsible for delivering Vitamin B-12 to tissues. The liver stores large amounts of Vitamin B-12. Enterohepatic reabsorption helps retain Vitamin B-12. Liver Vitamin B-12 stores can normally sustain physiologic needs for 3 to 5 years if B12 intake stops (eg, in people who become vegans) and for months to 1 year if enterohepatic reabsorption capacity is absent.

In healthy adults, vitamin B12 deficiency is uncommon, mainly because total body stores can exceed 2,500 mcg, daily turnover is slow, and dietary intake of only 2.4 mcg/day is sufficient to maintain adequate vitamin B12 status ⁹. In elderly individuals, vitamin B12 deficiency is more common mainly because of impaired intestinal absorption that can result in marginal to severe vitamin B12 deficiency in this population.

Vitamin B12 status is typically assessed by measurements of serum or plasma vitamin B12 levels ³⁹. The cutoff between normal vitamin B12 levels and vitamin B12 deficiency varies by method and laboratory, but most laboratories define subnormal serum or plasma values as those lower than 200 or 250 pg/mL (148 or 185 pmol/L) ¹⁴. Levels of serum methylmalonic acid (MMA), a vitamin B12-associated metabolite, are the most sensitive markers of vitamin B12 status, and an methylmalonic acid (MMA) level greater than 0.271 micromol/L suggests vitamin B12 deficiency ⁶⁰, ¹³, ⁶¹. However, MMA levels also rise with kidney failure and tend to be higher in older adults ⁶⁰, ²¹, ⁶². Another marker is total plasma homocysteine levels, which rise quickly as vitamin B12 status declines; a serum homocysteine level higher than 15 micromol/L, for example, suggests vitamin B12 deficiency ²⁰. However, this indicator has poor specificity because it is influenced by other factors, such as low folate levels and, especially, by declines in kidney function ⁶⁰. Experts suggest that if a patient’s serum vitamin B12 level is less than 150 pg/ml (111 pmol/L), the patient’s serum methylmalonic acid (MMA) levels should be checked to confirm a diagnosis of vitamin B12 deficiency ¹³, ²¹.

Vitamin B12 key points

Vitamin B12 or cobalamin plays essential roles in folate metabolism and in the synthesis of the citric acid cycle intermediate, succinyl-CoA.
Vitamin B12 deficiency is commonly associated with chronic stomach inflammation, which may contribute to an autoimmune vitamin B12 malabsorption syndrome called pernicious anemia and to a food-bound vitamin B12 malabsorption syndrome. Impairment of vitamin B12 absorption can cause megaloblastic anemia and neurologic disorders in deficient subjects.
Normal function of the digestive system required for food-bound vitamin B12 absorption is commonly impaired in individuals over 60 years of age, placing them at risk for vitamin B12 deficiency.
Vitamin B12 and folate are important for homocysteine metabolism. Elevated homocysteine levels in blood are a risk factor for cardiovascular disease. Although B vitamin supplementation has been proven effective to control homocysteine levels, current data from intervention trials have not shown that lowering homocysteine levels decreases cardiovascular disease risk.
The preservation of DNA integrity is dependent on folate and vitamin B12 availability. Poor vitamin B12 status has been linked to increased risk of breast cancer in some, but not all, observational studies. There is a need to evaluate whether supplemental vitamin B12, along with folic acid, could help reduce breast cancer incidence.
Low maternal vitamin B12 status has been associated with an increased risk of neural tube defects, but it is not known whether vitamin B12 supplementation could help reduce the risk of neural tube defects.
Vitamin B12 is essential for the preservation of the myelin sheath around neurons and for the synthesis of neurotransmitters. While hyperhomocysteinemia may increase the risk of cognitive impairment, it is not clear whether vitamin B12 deficiency contributes to the risk of dementia in the elderly. Although B-vitamin supplementation lowers homocysteine levels in older subjects, the long-term benefit is not yet known.
Both depression and osteoporosis have been linked to diminished vitamin B12 status and high homocysteine levels.
Products of animal origin constitute the primary source of vitamin B12. Older individuals and vegans are advised to use vitamin B12 fortified foods and supplements to meet their needs.
The long-term use of certain medications, such as inhibitors of stomach acid secretion, can adversely affect vitamin B12 absorption.

What does vitamin B12 do?

Vitamin B12 is required for the development, myelination, and function of the central nervous system; healthy red blood cell formation; and helps make DNA, the genetic material in all cells ¹⁵, ⁶³. Vitamin B12 functions as a cofactor for two enzymes, methionine synthase and L-methylmalonyl-CoA mutase (see more below) ¹⁵, ¹⁴, ⁶⁴. Methionine synthase catalyzes the conversion of homocysteine to the essential amino acid methionine ⁶⁵, ¹⁴. Methionine is required for the formation of S-adenosylmethionine, a universal methyl donor for almost 100 different substrates, including DNA, RNA, proteins, and lipids ¹⁵, ⁶⁴. L-methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to succinyl-CoA in the metabolism of propionate, a short-chain fatty acid ¹⁴.

Vitamin B12 functions as a cofactor for methionine synthase

Methylcobalamin is required for the function of the folate-dependent enzyme, methionine synthase. The methionine synthase enzyme is required for the synthesis of the amino acid, methionine, from homocysteine. Methionine in turn is required for the synthesis of S-adenosylmethionine (SAMe), a methyl group donor used in many biological methylation reactions, including the methylation of a number of sites within DNA, RNA, and proteins ⁶⁶. Aberrant methylation of DNA and proteins, which causes alterations in chromatin structure and gene expression, are a common feature of cancer cells. Inadequate function of methionine synthase can lead to an accumulation of homocysteine, which has been associated with increased risk of cardiovascular disease (Figure 4).

Figure 4. Vitamin B12 functions as a cofactor for methionine synthase

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Vitamin B12 functions as a cofactor for L-methylmalonyl-coenzyme A mutase

5-Deoxyadenosylcobalamin is required by the enzyme that catalyzes the conversion of L-methylmalonyl-coenzyme A to succinyl-coenzyme A (succinyl-CoA), which then enters the citric acid cycle (Figure 5). Succinyl-CoA plays an important role in the production of energy from lipids and proteins and is also required for the synthesis of hemoglobin, the oxygen-carrying pigment in red blood cells ⁶⁶.

Figure 5. Vitamin B12 functions as a cofactor for L-methylmalonyl-coenzyme A mutase

vitamin b12 in the production of energy and hemoglobin

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How much Vitamin B-12 do you need?

The amount of Vitamin B-12 you need each day depends on your age. Average daily recommended amounts for different ages are listed below in micrograms (mcg). Table 3 lists the current Recommended Dietary Allowance (RDA) for Vitamin B-12 in micrograms (mcg). For infants aged 0 to 12 months, the Food and Nutrition Board established an adequate intake (AI) for vitamin B-12 that is equivalent to the mean intake of Vitamin B-12 in healthy, breastfed infants.

Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.

Table 3. Vitamin B-12 Recommended Intake

Life Stage	Recommended Amount
Birth to 6 months	0.4 mcg
Infants 7–12 months	0.5 mcg
Children 1–3 years	0.9 mcg
Children 4–8 years	1.2 mcg
Children 9–13 years	1.8 mcg
Teens 14–18 years	2.4 mcg
Adults	2.4 mcg
Pregnant teens and women	2.6 mcg
Breastfeeding teens and women	2.8 mcg

[Source ⁶⁷ ].

What are food sources of vitamin B12?

Vitamin B12 is found naturally in a wide variety of foods of animal origin (such as fish, meat, poultry, eggs, and dairy products) and manufacturers add it to some fortified foods (e.g., fortified breakfast cereals and fortified nutritional yeasts) ¹⁵. Plant foods have no vitamin B12 unless they are fortified ⁶⁸. You can get recommended amounts of vitamin B12 by eating a variety of foods including the following:

Fish, meat, poultry, eggs, milk, and other dairy products contain vitamin B12.
Clams and beef liver are some of the best source of vitamin B12.
Some breakfast cereals, nutritional yeasts, and other food products are fortified with vitamin B12.

The U.S. Department of Agriculture’s FoodData Central (https://fdc.nal.usda.gov) lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin B12 arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/VitaminB12-Content.pdf) and by food name (https://ods.od.nih.gov/pubs/usdandb/VitaminB12-Food.pdf).

The average vitamin B12 level in the breast milk of women with vitamin B12 intakes above the RDA is 0.44 mcg/L ⁶⁹. The U.S. Food and Drug Administration (FDA) specifies that infant formulas sold in the United States must provide at least 0.15 mcg vitamin B12 per 100 kcal ⁷⁰.

The estimated bioavailability of vitamin B12 from food varies by vitamin B12 dose because absorption decreases drastically when the capacity of intrinsic factor is exceeded (at 1–2 mcg of vitamin B12) ⁷¹. Bioavailability also varies by type of food source. For example, the bioavailability of vitamin B12 appears to be about three times higher in dairy products than in meat, fish, and poultry, and the bioavailability of vitamin B12 from dietary supplements is about 50% higher than that from food sources ⁷².

A variety of foods and their vitamin B12 levels per serving are listed in Table 4.

Table 4. Vitamin B12 Food Sources

Food	Micrograms per serving	Percent DV*
Beef liver, cooked, pan-fried, 3 ounces	70.7	2944
Clams (without shells), cooked, 3 ounces	17	708
Tuna, bluefin, cooked, dry heat, 3 ounces	9.3	385
Nutritional yeast, fortified, from several brands (check label), about ¼ cup	8.3 to 24	346 to 1,000
Salmon, Atlantic, cooked, 3 ounces	2.6	108
Beef, ground, 85% lean meat/15% fat, pan-browned, 3 ounces	2.4	100
Milk, 2% milkfat, 1 cup	1.3	54
Yogurt, plain, fat free, 6-ounce container	1	43
Breakfast cereals, fortified with 25% of the DV for vitamin B12, 1 serving	0.6	25
Cheese, cheddar, 1½ ounces	0.5	19
Egg, whole, cooked, 1 large	0.5	19
Turkey, breast meat, roasted, 3 ounces	0.3	14
Tempeh, 1/2 cup	0.1	3
Banana, 1 medium	0	0
Bread, whole-wheat, 1 slice	0	0
Strawberries, raw, halved, 1/2 cup	0	0
Beans, kidney, boiled, 1/2 cup	0	0
Spinach, boiled, drained, 1/2 cup	0	0

Footnote: *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers determine the level of various nutrients in a standard serving of food in relation to their approximate requirement for it. The DV for Vitamin B-12 is 6.0 mcg. However, the FDA does not require food labels to list Vitamin B-12 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

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Who are at risk of vitamin B12 deficiency?

The following people are among those most likely to be vitamin B12 deficient.

Older adults

Depending on the definition used, between 3% and 43% of community-dwelling older adults, especially those with atrophic gastritis (chronic inflammation and thinning of your stomach), have vitamin B12 deficiency based on serum vitamin B12 levels ⁷⁴, ⁷⁵. The vitamin B12 deficiency rate at a cutoff of less than 211 mcg/L (156 pmol/L) at admission to a long-term care facility, according to one study, was 14%, and 38% of these older adults had levels lower than 407 pg/mL (300 pmol/L) ⁷⁵.

Conditions associated with vitamin B12 deficiency include pernicious anemia, present in about 15% to 25% of older adults with vitamin B12 deficiency ⁴². Atrophic gastritis, an autoimmune condition affecting 2% of the general population but 8–9% of adults aged 65 and older, decreases production of intrinsic factor and secretion of hydrochloric acid in the stomach and thus decreases absorption of vitamin B12 ⁴², ⁷⁶. A third condition associated with vitamin B12 deficiency in older adults is Helicobacter pylori infection, possibly because this bacterium causes inflammation that leads to malabsorption of vitamin B12 from food ⁷⁷.

Individuals with pernicious anemia

Pernicious anemia is an irreversible autoimmune disease that affects the gastric mucosa and results in gastric atrophy ⁷⁸. This disease leads to attacks on parietal cells in the stomach, resulting in failure to produce intrinsic factor (IF) and malabsorption of dietary vitamin B12, recycled biliary vitamin B12, and free vitamin B12 ⁷⁹, ⁶⁰. Therefore, without treatment, pernicious anemia causes vitamin B12 deficiency, even in the presence of adequate vitamin B12 intakes.

Pernicious anemia is the most common cause of clinically evident vitamin B12 deficiency around the world ⁷⁹, ⁷⁸. The incidence of pernicious anemia in the United States is an estimated 151 per 100,000, and this condition is more common in women and in people of European ancestry ⁷⁸.

Individuals with gastrointestinal disorders

Individuals with stomach and small intestine disorders, such as celiac disease and Crohn’s disease, may be unable to absorb enough vitamin B12 from food to maintain healthy body stores ⁸⁰. But although rates of vitamin B12 deficiency are higher in people with celiac disease than other people ⁸¹, the evidence for whether rates of vitamin B12 deficiency are higher in people with Crohn’s disease is mixed ⁸², ⁸³. Vitamin B12 deficiency in people with Crohn’s disease is typically treated with intramuscular cobalamin injections, but high doses of oral cyanocobalamin therapy (e.g., 1,000 mcg/day) might be equally effective ⁸⁴.

Individuals who have had gastrointestinal surgery

Surgical procedures in the gastrointestinal tract, such as for weight loss (bariatric surgery) or to remove all or part of the stomach (gastrectomy), can cause a complete or partial loss of cells that secrete hydrochloric acid and cells that secrete intrinsic factor (IF) ⁸⁵, ⁸⁶. Thus, these procedures reduce the amount of vitamin B12, particularly food-bound vitamin B12, that the body absorbs ⁸⁵, ⁸⁶. High doses (1,000 mcg/day) of oral methylcobalamin supplements appear to be as effective as hydroxycobalamin injections in normalizing vitamin B12 values in patients who have undergone Roux-en-Y gastric bypass surgery ⁸⁷.

Vegetarians

Vegans who consume no animal products and vegetarians who consume some animal products (e.g., dairy products, eggs, or both) but not meat have a higher risk of developing vitamin B12 deficiency because natural food sources of vitamin B12 are limited to animal foods ⁸⁸. Consumption of foods fortified with vitamin B12 (such as fortified nutritional yeasts) as well as vitamin B12 supplements can substantially reduce the risk of deficiency ⁸⁸.

Infants of vegan women

Exclusively breastfed infants of women who consume no animal products might have very limited reserves of vitamin B12 and can develop vitamin B12 deficiency, sometimes very early in life ⁸⁹. The infant’s vitamin B12 deficiency can be severe, especially if the mother’s vitamin B12 deficiency is severe or caused by pernicious anemia; sometimes, the mother’s own vitamin B12 deficiency is clinically mild and not recognized. Undetected and untreated vitamin B12 deficiency in infants can result in neurological damage, failure to thrive, developmental delays, and anemia ⁸⁹, ⁹⁰. The reasons include the small amounts of vitamin B12 in the breast milk of vegan mothers as well as the limited amounts of vitamin B12 crossing the placenta in these women during fetal development.

What is pernicious anemia?

Pernicious anemia is an irreversible auto-immune disease that affects the gastric mucosa (autoimmune gastritis) and results in gastric atrophy ⁷⁸, ⁹¹, ⁹². People who have pernicious anemia can’t absorb enough vitamin B12 from food. This is because they lack intrinsic factor (IF), a protein made in your stomach. A lack of intrinsic factor (IF) leads to vitamin B12 deficiency. In pernicious anemia your own antibodies attack the parietal cells in your stomach, resulting in failure to produce intrinsic factor (IF) and malabsorption of dietary vitamin B12, recycled biliary vitamin B12, and free vitamin B12 ⁹³, ⁷⁹, ⁶⁰. Progressive destruction of the parietal cells that line your stomach cause decreased secretion of acid and enzymes required to release food bound vitamin B12. Antibodies to intrinsic factor (IFA) bind to IF preventing formation of the IF-B12 complex, further inhibiting vitamin B12 absorption. Without enough vitamin B12, your red blood cells don’t divide normally and are too large (megaloblasts). These changes occur because vitamin B12 is necessary for DNA synthesis ⁹⁴. Pernicious anemia is one of two major types of “macrocystic” or “megaloblastic” anemia. These terms refer to anemia in which the red blood cells are larger than normal. The other major type of macrocystic anemia is caused by folic acid deficiency. In addition to megaloblasts, hypersegmented neutrophils are also present. The large red blood cells may have trouble getting out of the bone marrow—a sponge-like tissue inside the bones where blood cells are made. Megaloblastic anemia is characterized by large nucleated red blood cell precursors called megaloblasts in the bone marrow ⁹⁴. Without enough red blood cells to carry oxygen to your body, you may feel tired and weak. Severe or long-lasting pernicious anemia can damage the heart, brain, and other organs in the body. Note that the causes of megaloblastic anemia other than vitamin B12 deficiency caused by impaired intrinsic factor (IF) production can include folic acid deficiency, altered pH in the small intestine, and lack of absorption of vitamin B12 complexes in the terminal ileum. Thus, pernicious anemia must be differentiated from other disorders that interfere with the absorption and metabolism of vitamin B12.

Pernicious anemia has often been confused with vitamin B12 deficiency ⁹⁵. Pernicious anemia denotes only vitamin B12 deficiency due to gastric atrophy and/or intrinsic factor deficiency or autoimmune gastritis ⁹⁵. Pernicious anemia is considered a late stage of autoimmune gastritis.

The pathogenesis of pernicious anemia has not been clarified, but it is likely linked to the autoimmune destruction of gastric glands due to autoreactive T lymphocytes in genetically predisposed individuals ⁹⁵. The role of previous Helicobacter pylori (H. pylori) infection as a supposed but not yet definitely proven trigger of gastric autoimmunity cannot be excluded ⁹⁵. Hershko et al. ⁹⁶ have reported that H. pylori might serve as a trigger of autoimmune metaplastic atrophic gastritis and pernicious anemia, based on their observation that the prevalence of H. pylori infection was 87.5% in patients under 20 years of age. In addition, one theory regarding the initiating event of autoimmune metaplastic atrophic gastritis is molecular mimicry between H. pylori antigens and gastric H+/K+−ATPase ⁹⁷.

In pernicious anemia, the underlying pathogenetic mechanism is autoimmune gastritis, an organ-specific immune-mediated disorder featuring the damage of the gastric parietal cells involved in the secretion of intrinsic factor (IF) and hydrochloric acid by the gastric proton pump ⁹⁸. The presence of anti-parietal cell antibodies (PCAs) directed towards the gastric proton pump (gastric hydrogen potassium adenosine triphosphatase (H+/K+ ATPase)) as well as antibodies against intrinsic factor (IF) (although in a lower percentage) are commonly associated with gastric corpus atrophy and intrinsic factor deficiency ⁹⁵, ⁹⁹. Atrophic corpus gastritis is a chronic disease defined as a decrease in or loss of the original gastric glands, replaced by pseudo-pyloric or intestinal metaplasia or fibrosis ¹⁰⁰. Gastric corpus atrophy is a necessary but insufficient condition for the onset of pernicious anemia, as gastric corpus atrophy may also take its course without pernicious anemia.

In rare cases, pernicious anemia is passed down through families (inherited disorder). This is called congenital pernicious anemia ⁹⁵. Babies with congenital pernicious anemia do not make enough intrinsic factor (IF). Or they cannot properly absorb vitamin B12 in the small intestine. Congenital pernicious anemia is quite rare and distinguishable from the usual form of pernicious anemia due to the early age of onset and the absence of gastric corpus atrophy.

Pernicious anemia can also cause other problems, such as nerve damage, neurological problems (such as memory loss), and digestive tract problems. People who have pernicious anemia also may be at higher risk for weakened bone strength (osteoporosis) and stomach cancer. Pernicious anemia is frequently presenting with other autoimmune conditions such as autoimmune thyroid disease, type 1 diabetes, and vitiligo ¹⁰¹.

Without treatment, pernicious anemia causes vitamin B12 deficiency, even in the presence of adequate vitamin B12 intakes. Generally, it takes about 10–12 years to clinically develop symptomatic pernicious anemia, so pernicious anemia may onset with subclinical vitamin B12 deficiency ¹⁰².

Pernicious anemia is the most common cause of clinically evident vitamin B12 deficiency around the world ⁷⁹, ⁷⁸. Pernicious anemia accounts for 20%‐50% of the vitamin B12 deficiency in adults ¹⁰³. The incidence of pernicious anemia in the United States is an estimated 151 per 100,000, and this condition is more common in women and in people of European ancestry (North Europeans and Caucasian Americans) ⁷⁸. The prevalence of pernicious anemia in Japan is rare, 1 to 5 per 100,000 persons ¹⁰⁴, compared with the West.

An important point is that pernicious anemia may lead to potentially serious long-term complications that may be related to micronutrient deficiencies and the development of gastric neoplasms, in particular, gastric cancer and type 1 gastric neuroendocrine tumors ⁹⁵. When not recognized in a timely manner or when pernicious anemia is diagnosed with delay, these complications may be potentially life-threatening and sometimes irreversible.

Vitamin B12 therapy resolves the anemia of pernicious anemia, but does not cure the atrophic gastritis, which can progress to gastric cancer ¹⁰⁵. The incidence of gastric adenocarcinoma is 2- to 3-fold greater in patients with pernicious anemia than in the general population of the same age ¹⁰⁶. Presently, periodic gastroscopy and/or barium studies are not advocated in patients with treated pernicious anemia who are asymptomatic, because such screening has not been demonstrated to prolong lifespan ¹⁰⁶.

A population-based, case-control study using the Surveillance, Epidemiology, and End Results (SEER)–Medicare database found that elderly persons with pernicious anemia were not only at significantly increased risk for noncardia gastric adenocarcinoma and gastric carcinoid tumors, they were also at increased risk for the following ¹⁰⁵:

Tonsillar cancer
Hypopharyngeal cancer
Esophageal squamous cell carcinoma
Small intestinal cancer
Liver cancer
Myeloma
Acute myeloid leukemia
Myelodysplastic syndrome

In a longitudinal study of 199 intrinsic factor antibody (IFA)–positive and 168 IFA-negative Chinese patients, Chan et al ¹⁰⁷ found that despite a good hematologic response to therapy, both groups had an unsatisfactory neurologic response, and newly diagnosed hypothyroidism was found during follow-up. In addition, newly diagnosed cancers were also found (24 in IFA-positive patients, seven in IFA-negative patients), of which 20% were stomach cancer ¹⁰⁷.

For the intrinsic factor antibody (IFA)-positive patients with a cancer, mean survival was 64 months; for those without a cancer, it was 129 months. Mortality was 31% in this group, in which cancer-related deaths represented 37% of the total ¹⁰⁷. For the intrinsic factor antibody (IFA)-negative patients with a cancer, mean survival was 36 months. For those without a cancer, it was 126 months. Mortality was 21% in this group, in which cancer-related deaths represented 14% of the total.

Chan et al ¹⁰⁷ concluded that although Chinese patients treated for pernicious anemia demonstrated a good survival period, they remained at increased risk for gastric carcinoma, and IFA-positive patients had a higher risk of developing all types of cancers and cancer-related deaths than did IFA-negative patients.

Pernicious anemia has been estimated to be present in approximately 2% of individuals over 60 years of age ¹⁰⁸. Although anemia is often a symptom, the condition is actually the end stage of an autoimmune inflammation of the stomach known as autoimmune atrophic gastritis, resulting in destruction of stomach cells by one’s own antibodies (autoantibodies). Progressive destruction of the cells that line the stomach causes decreased secretion of acid and enzymes required to release food-bound vitamin B12. Antibodies to intrinsic factor (IF) bind to IF preventing formation of the IF-B12 complex, further inhibiting vitamin B12 absorption. About 20% of the relatives of pernicious anemia patients also have the condition, suggesting a genetic predisposition. It is also thought that H. pylori infection could be involved in initiating the autoimmune response in a subset of individuals ¹⁰⁹. Further, co-occurrence of autoimmune atrophic gastritis with other autoimmune conditions, especially autoimmune thyroiditis and type 1 diabetes mellitus, has been reported ¹¹⁰.

Pernicious anemia signs and symptoms are similar to other vitamin B12 deficiencies, but pernicious anemia is sometimes associated with other autoimmune diseases such as type 1 diabetes, autoimmune thyroiditis, and Addison’s disease.

When pernicious anemia is suspected, the first step is usually a full blood panel to test for anemia and/or macrocytosis, together with testing for cobalamin deficiency and increased levels of homocysteine and/or methylmalonic acid (MMA) ⁹⁵. Next, the positivity of gastric autoantibodies towards parietal cells and/or intrinsic factor (IF) is commonly assessed ⁹⁵. Sensitivity and specificity of the anti‐intrinsic factor antibody test were 50%‐70%, and greater than 95%, respectively ¹¹¹. Sensitivity and specificity of the antigastric parietal cell antibody test were more than 90% and 50%, respectively ¹¹². In any case, the hematological and/or serological suspicion of pernicious anemia always needs to be confirmed by histological assessment of gastric antral and corpus biopsies obtained during gastroscopy to ascertain the presence of autoimmune gastritis ⁹⁵.

The treatment for pernicious anemia is lifelong administration of vitamin B12. Treatment of pernicious anemia generally requires injections of vitamin B12 to bypass intestinal absorption. High-dose oral supplementation is another treatment option, because consuming 1,000 mcg (1 mg)/day of vitamin B12 orally should result in the absorption of about 10 mcg/day (1% of dose) by passive diffusion. In fact, high-dose oral therapy is considered to be as effective as intramuscular injection ⁹.

Patients with pernicious anemia are at high risk of developing stomach cancer such as gastric adenocarcinoma and carcinoid tumors ¹¹³. Significant risk factors for the development of gastric carcinoma in autoimmune metaplastic atrophic gastritis include the presence of pernicious anemia, severity of mucosal atrophy, intestinal metaplasia, disease duration, and over 50 years of age ¹¹⁴. Periodic stomach examinations are recommended for patients with pernicious anemia.

Pernicious anemia causes

Pernicious anemia is an autoimmune disorder. Typically, pernicious anemia is associated with the presence of autoantibodies against intrinsic factor (anti-intrinsic factor antibody or IFA) and anti-parietal cell antibodies (PCA), thus supporting the autoimmune origin of this condition ¹¹⁵. Anti-parietal cell antibodies (PCA) are seen in up to 85% of patients with pernicious anemia ¹¹⁶. However, the anti-parietal cell antibody (PCA) is not specific for pernicious anemia and can be seen in 3 to 10% of normal healthy populations without any evidence of megaloblastic anemia ¹¹⁶. Antibodies against parietal cells (PCA) are class M, G, and A immunoglobulins directed towards the alpha and beta subunits of the gastric proton pump (hydrogen-potassium ATP-ase) ¹¹⁷. Anti-intrinsic factor antibodies (IFA) are seen in 40 to 60% of the patients with pernicious anemia and are highly specific for the disease ¹¹⁶. Antibodies against intrinsic factor (IFA) are class G immunoglobulins that target the binding site for cobalamin (type I) or the binding site for ileal epithelial mucosa (type II) ¹¹⁸. These autoantibodies are released from plasma cells activated by autoreactive CD4+ T cell lymphocytes in perigastric lymph nodes ¹¹⁹. These triggered CD4+ T cells target the proton pump ATPases, which leads to their immune destruction ¹¹⁶. Atrophic gastritis with loss of parietal cells and subsequent intrinsic factor (IF) deficiency develops. This leads to vitamin B12 deficiency and the onset of symptoms associated with pernicious anemia. Gastric dendritic cells are responsible for the activation of lymphocytes that lead to the production of these antibodies. The cause and mechanism of dendritic cell activation are not yet clarified ¹¹⁶. Some research studies suggest Helicobacter pylori (H. pylori) infection is a trigger in genetically susceptible individuals ¹²⁰. The studies propose molecular mimicry and immune cross-reactivity between the proton pump ATPase and the H. pylori antigens as a triggering event ¹²⁰. A 2017 review evaluating H. pylori antigenic mimicry stated that these antigens play an important role in the induction of humoral and cellular immune responses, which may predispose patients to pathological inflammatory responses ¹²¹.

These circulating anti-intrinsic factor antibodies (IFA) and anti-parietal cell antibodies (PCA) cause autoimmune chronic atrophic gastritis with parietal cell loss and eventual vitamin B12 deficiency ¹¹⁶. However, autoimmune gastritis-associated gastric corpus atrophy may progress without developing pernicious anemia ⁹⁵.

Pernicious anemia can be associated with other autoimmune diseases and in patients with polyglandular autoimmune disorders. Autoimmune diseases associated with pernicious anemia include type 1 diabetes (3 to 4%), vitiligo (2 to 8%), and autoimmune thyroid disease (3 to 32%) ¹¹⁵. Type III polyglandular autoimmune syndrome is characterized by the presence of autoimmune thyroiditis, vitiligo, alopecia, type 1A diabetes mellitus, pernicious anemia, and chronic atrophic gastritis ¹²². HLA alleles are thought to play a role in the pathogenesis of these autoimmune disorders, but the mechanism is not entirely understood. HLA-DRB1/03 and HLA-DRB1/04 alleles may predispose to autoimmune gastritis and subsequent pernicious anemia ¹¹⁵.

There is an overlap in patients infected with Helicobacter pylori (H. pylori) and the development of chronic atrophic gastritis associated with pernicious anemia ¹²³. Researchers propose H. pylori peptide-induced gastric T-cell proliferation as the cause of pernicious anemia in some patients ¹²⁰. They were able to demonstrate the presence of activated T cells in the gastric mucosa of patients with autoimmune chronic atrophic gastritis and H. pylori infection. These T cells reacted to both hydrogen-potassium-ATPase and H. pylori ¹²⁰. Recent experimental and clinical data suggest long-standing H. pylori infection plays a pivotal role in developing atrophic gastritis and subsequent pernicious anemia; however, convincing data to support H. pylori infection as a definite cause of pernicious anemia is still lacking ¹¹⁵. Molecular analyses have revealed hydrogen-potassium-ATPase epitopes that are similar to, or cross-reactive with, epitopes of H. pylori antigens. Thus suggesting that in genetically susceptible individuals, H. pylori infection can trigger gastric autoimmunity via molecular mimicry ¹²⁰.

A heritable form of pernicious anemia called “childhood pernicious anemia” is seen in children with a genetic defect that leads to decreased IF production or abnormal IF formation ⁹⁵. This condition is quite rare and distinguishable from the usual form of pernicious anemia due to the early age of onset and the absence of gastric corpus atrophy.

Risk factors for pernicious anemia

Pernicious anemia is more common in people of Northern European and African descent than in other ethnic groups.

Older people also are at higher risk for the condition. This is mainly due to a lack of stomach acid and intrinsic factor, which prevents the small intestine from absorbing vitamin B12. As people grow older, they tend to make less stomach acid.

Pernicious anemia also can occur in younger people and other populations. You’re at higher risk for pernicious anemia if you:

Have a family history of the condition.
Have had part or all of your stomach surgically removed. The stomach makes intrinsic factor. This protein helps your body absorb vitamin B12.
Have an autoimmune disorder that involves the endocrine glands, such as Addison’s disease, type 1 diabetes, Graves’ disease, or vitiligo. Research suggests a link may exist between these autoimmune disorders and pernicious anemia that’s caused by an autoimmune response.
Have had part or all of your small intestine surgically removed. The small intestine is where vitamin B12 is absorbed.
Have certain intestinal diseases or other disorders that may prevent your body from properly absorbing vitamin B12. Examples include Crohn’s disease, intestinal infections, and HIV.
Take medicines that prevent your body from properly absorbing vitamin B12. Examples of such medicines include antibiotics and certain seizure medicines.
Are a strict vegetarian who doesn’t eat any animal or dairy products and doesn’t take a vitamin B12 supplement, or if you eat poorly overall.

Pernicious anemia prevention

Because an increased familial incidence of pernicious anemia exists, family members should be aware that they are at greater risk of developing this disease and should seek medical attention promptly if they develop anemia or mental and neurologic symptoms ¹²⁴. Monitor siblings and children of patients with a hereditary abnormality of vitamin B12 deficiency for evidence of the specific defect in cobalamin transport or metabolism.

Determine whether vitamin B12 deficiency is the cause in patients who recently developed evidence of mental deterioration.

Prophylactically treat patients with vitamin B12 when they have undergone total gastrectomy, bypass procedures for weight reduction, ileectomy, pancreatectomy, or when they have atrophic gastritis or chronic inflammatory disease of the ileum ¹²⁴.

Strict vegetarians should continue supplementary vitamin B12, particularly during pregnancy and while nursing a newborn infant ¹²⁴.

Elderly people are at risk for developing pernicious anemia due to achlorhydria. Therefore, serum vitamin B-12 levels should be checked. If low or if cobalamin deficiency is suspected, they should be treated with vitamin B-12 supplementation.

Pernicious anemia signs and symptoms

The onset of pernicious anemia usually is insidious and vague. The main signs and symptoms of pernicious anemia are hematological and neurological consequences of vitamin B12 deficiency, and both require several years for their development. The classic presentation consists of a triad of jaundice, glossitis, and myeloneuropathy ¹²⁵. However, with advances in clinical detection and often routine laboratory testing, this classic triad of jaundice, glossitis, and myeloneuropathy is now a rarity. Many pernicious anemia patients are incidentally noted to have macrocytic anemia and are ultimately diagnosed with this condition. Others may either present with symptoms attributable to anemia, such as lethargy and inability to concentrate, or with symptoms attributable to neuronal damage, such as paresthesias, imbalance, and spasticity ¹¹⁶.

Figure 6. Pernicious anemia signs and symptoms (related to hypochlorhydria and vitamin B12 deficiency)

[Source ⁹⁵ ]

General symptoms

Weight loss of 10-15 lb occurs in about 50% of patients and probably is due to anorexia, which is observed in most patients. Low-grade fever occurs in one third of newly diagnosed patients and promptly disappears with treatment.

Heart symptoms

Individuals with pernicious anemia often tolerate the anemia well, and many are ambulatory with hematocrit levels in the mid-teens. However, the cardiac output is usually increased when hematocrit levels fall below 20%, with associated accerations in heart rate. Congestive heart failure and coronary insufficiency can occur, most particularly in patients with preexisting heart disease.

Gastrointestinal symptoms

Approximately 50% of patients with pernicious anemia develop atrophic glossitis, presenting with a smooth tongue that may be painful and beefy red, with loss of papillae that is usually most marked along the edges of the tongue ¹²⁶. These patients report burning or soreness, most particularly on the anterior third of the tongue, associated with changes in taste and loss of appetite ⁴¹.

Patients may report either constipation or having several semisolid bowel movements daily. These symptoms have been attributed to megaloblastic changes of the cells of the intestinal mucosa.

Nonspecific gastrointestinal symptoms are not unusual and include anorexia, nausea, vomiting, heartburn, pyrosis, flatulence, and a sense of fullness ¹²⁷. Rarely, patients present with severe abdominal pain associated with abdominal rigidity; this has been attributed to spinal cord pathology. Venkatesh and colleagues ¹²⁸ report the case of a patient who presented with epigastric pain, diarrhea, and vomiting and was found to have thrombosis of the portal, superior mesenteric, and splenic veins due to hyperhomocysteinemia secondary to pernicious anemia.

Neurologic symptoms

The most common neurologic symptoms in vitamin B12 deficiency include paresthesias, weakness, clumsiness, and an unsteady gait. The last two symptoms are exacerbated in dark environments due to the loss of visual cues that patients often rely on, in concert with the loss of proprioception. These neurologic symptoms are due to myelin degeneration and loss of nerve fibers in the dorsal and lateral columns of the spinal cord and cerebral cortex (subacute combined degeneration).

Neurologic symptoms and findings may be present in the absence of anemia. This is more common in patients taking folic acid or on a high-folate diet.

Older patients may present with symptoms suggesting senile dementia or Alzheimer disease; memory loss, irritability, and personality changes are commonplace ¹¹⁶. Common psychiatric manifestations include depression, mania, chronic fatigue syndrome, and psychosis ⁹⁵. Cognitive symptoms include memory impairment, attention deficit, and dementia ⁹⁵. So-called megaloblastic madness—delusions, hallucinations, outbursts, and paranoid schizophrenic ideation—is less common. Identifying the cause is important because significant reversal of these symptoms and findings can occur with vitamin B12 administration.

While neurologic symptoms usually occur in the elderly, they can rarely occur in the young ¹²⁹. Kocaoglu et al. ¹³⁰ reported a case of vitamin B12 deficiency and cerebral atrophy in a 12-month-old infant whose development had slowed since 6 months of age; the infant was exclusively breastfed and his mother was a long-time vegetarian. Neurologic recovery began within days after the infant received an intramuscular cobalamin injection.

Genitourinary symptoms

Urinary retention and impaired micturition may occur because of spinal cord damage. This can predispose patients to urinary tract infections.

Symptoms of thrombotic complications

A study of four patients revealed that pernicious anemia can lead to hyperhomocysteinemia that is significant enough to lead to venous thrombosis, even in the absence of any other risk factors for thromboembolism ¹³¹.

Pernicious anemia complications

One of the most dreaded complications of pernicious anemia is the development of gastric cancer ¹⁰⁵. A 2013 systematic review of over 22,000 patients with pernicious anemia found a pooled gastric cancer incidence of 0.27% per person-year, with a nearly sevenfold increased risk of gastric cancer in these patients ¹³². The same study showed a pooled gastric cancer recurrence rate of 6.8 ¹³². For this reason, an upper gastrointestinal endoscopy is recommended when pernicious anemia is diagnosed ¹¹⁵. Repeat endoscopies without any evidence of gastrointestinal symptoms are generally not recommended. Surveillance endoscopy every three years is recommended by some experts in patients with documented evidence of advanced chronic autoimmune atrophic gastritis ¹³³.

According to a large United States population study based on a Surveillance, Epidemiology, and End Results (SEER) Medicare database, patients with pernicious anemia are at higher risk of 10 cancer types ¹⁰⁵:

Gastric adenocarcinoma
Gastric carcinoid tumors
Tonsillar cancer
Hypopharyngeal cancer
Esophageal squamous cell carcinoma
Myeloma
Acute myeloid leukemia
Myelodysplastic syndrome

The authors state, “The most striking of our findings was an 11-fold increase in the risk of gastric carcinoid tumors for both men and women with pernicious anemia, a risk that was higher among cases occurring 6 or more years after the pernicious anemia report/diagnosis” ¹⁰⁵. They also point out these are uncommon cancers with low absolute risk: “Of the 17,076 cancers in our study among people with pernicious anemia, just 83 (0.5%) were gastric carcinoid tumors” ¹⁰⁵.

Pernicious anemia diagnosis

When pernicious anemia is suspected, the first step is usually a full blood panel to test for anemia and/or macrocytosis, together with testing for vitamin B12 deficiency and increased levels of homocysteine and/or methylmalonic acid (MMA). Next, the positivity of gastric autoantibodies towards parietal cells and/or intrinsic factor is commonly assessed. In any case, the hematological and/or serological suspicion of pernicious anemia always needs to be confirmed by histological assessment of gastric antral and corpus biopsies obtained during gastroscopy ⁹⁵.

The workup for pernicious anemia may include the following ¹³⁴:

Complete blood cell count (CBC)
Peripheral blood smear
Indirect bilirubin and lactate dehydrogenase assays
Evaluation of gastric secretions. Total gastric secretions are decreased to about 10% of the reference range. Most patients with pernicious anemia are achlorhydric, even with histamine stimulation. Intrinsic factor (IF) is either absent or markedly decreased.
Serum vitamin B12 (cobalamin), folic acid, methylmalonic acid (MMA) and homocysteine assays.
- Serum cobalamin reference ranges may vary slightly among different laboratories, but are generally from 200–900 pg/mL. Values of 180-250 pg/mL are considered bordeline, while less than 150 pg/mL is considered diagnostic of vitamin B12 deficiency. In these cases, elevated levels of methylmalonic acid (MMA) and total homocysteine can confirm the diagnosis ³³.
- The serum cobalamin level is usually low in patients with pernicious anemia. However, up to a third of patients can present with normal vitamin B12 levels and normocytic anemia, which often delays diagnosis ¹³⁵. Certain patients with other forms of cobalamin deficiency, such as some inborn forms of cobalamin deficiency, transcobalamin 2 deficiency, and cobalamin deficiency due to nitrous oxide, can also present with normal serum cobalamin levels.
- Serum cobalamin levels may also be low in patients with no clinical or identifiable metabolic abnormality ³⁸. Causes of falsely low serum cobalamin levels inclue the following:
  - Pregnancy
  - Oral contraceptives and hormone replacement therapy
  - Multiple myeloma
  - Transcobalamin 1 (TC1) deficiency
  - Severe folic acid deficiency
  - Ascorbic acid in high doses
- A serum folic acid assay is useful for ruling out folic acid deficiency. The reference range is 2.5-20 ng/mL. Blood should be drawn before patients have a single hospital meal since food can restore serum folic acid levels to normal. Red blood cell folic acid level is not influenced by food.
Levels of antibodies against intrinsic factor (IF) or the cells which make intrinsic factor (anti-parietal cell antibodies [PCAs]).
Schilling test (no longer available in most medical centers)
A clinical trial of vitamin B12
Patients with diagnosis of pernicious anemia should undergo gastroscopy with biopsies to ascertain the presence of autoimmune gastritis ⁹⁵. Biopsies should be collected following the updated Sydney system ¹³⁶: two biopsies of the antrum and two biopsies from the corpus should be obtained and sent in separate vials. Another biopsy should be performed from incisura angularis and sent in the same vial of antrum biopsies.
Bone marrow aspiration and biopsy (only needed if diagnosis is unclear)

Complete blood cell count (CBC) and peripheral blood smear may show the mean corpuscular volume (MCV) and mean cell hemoglobin (MCH) are increased, with a mean corpuscular hemoglobin concentration (MCHC) within the reference range ¹³⁴. However, up to 30% of patients with pernicious anemia may lack macrocytosis ⁹⁵. A normal MCV (mean corpuscular volume) does not rule out megaloblastic anemia, and pathognomonic megaloblasts are rarely seen. The hematocrit must fall by 20% before megaloblasts appear in the blood ¹²⁵. Anisocytosis and an increase in the red cell distribution width is the earliest measurable change in red cell indices to hint toward the diagnosis ¹²⁵.

The peripheral blood usually shows a macrocytic anemia with a mild leukopenia and thrombocytopenia. The leukopenia and thrombocytopenia usually parallel the severity of the anemia. The peripheral smear shows oval macrocytes, hypersegmented granulocytes, and anisopoikilocytosis. In severe anemia, red blood cell inclusions may include Howell-Jolly bodies, Cabot rings, and punctate basophilia. The macrocytosis can be obscured by the coexistence of iron deficiency, thalassemia minor, or inflammatory

The indirect bilirubin level may be elevated because pernicious anemia is a hemolytic disorder associated with increased turnover of bilirubin ¹³⁴. The serum lactate dehydrogenase (LDH) concentration usually is markedly increased ¹³⁴. Increased values for other red blood cells, enzymes, and serum iron saturation also are observed. The serum potassium, cholesterol, and skeletal alkaline phosphatase often are decreased.

A significantly decreased serum cobalamin level along with a typical clinical presentation, a characteristic peripheral smear, and an increased indirect bilirubin and LDH level is sufficient evidence for the diagnosis of a megaloblastic anemia.

Serum methylmalonic acid and homocysteine tests are important confirmatory tests but are not first-line tests. Elevated serum methylmalonic acid and homocysteine levels are found in patients with pernicious anemia. They probably are the most reliable test for cobalamin deficiency in patients who do not have a congenital metabolism disorder. In the absence of an inborn error of methylmalonic acid metabolism, methylmalonic aciduria is a sign of cobalamin deficiency.

Table 5. Serum methylmalonic acid (MMA) and homocysteine values used in differentiating between vitamin B12 deficiency and folic acid deficiency

Patient Condition	Methylmalonic Acid	Homocysteine
Healthy	Normal	Normal
Vitamin B12 deficiency	Elevated	Elevated
Folate deficiency	Normal	Elevated

[Source ¹³⁷ ]

Testing for B12 Deficiency

A B12 level below 200 pg/mL (ng/L) is consistent with vitamin B12 deficiency ¹²³. Levels between 200 to 400 pg/mL are considered borderline ¹¹⁶. Serum B12 measurement alone has poor sensitivity and specificity for detecting B12 deficiency ¹²⁵. In patients with pernicious anemia, this level will be falsely elevated in 22 to 35% of the patients due to the interaction of IF antibody (IFA) with the “IF reagent” used to detect B12 levels in current assays ¹¹⁶. Falsely low serum vitamin B12 levels can occur in patients with underlying multiple myeloma and pregnancy ³⁸, ¹¹⁶.

Methylmalonic acid (MMA) and homocysteine levels can be obtained in patients when vitamin B12 levels are borderline or nondiagnostic to confirm the diagnosis of B12 deficiency ¹³⁸. These assays are considered more sensitive and specific for detecting B12 deficiency when compared to serum B12 levels ¹²⁵. Methylmalonic acid (MMA) can also help differentiate between vitamin B12 and folate deficiency, as it is elevated in vitamin B12 deficiency but not in folate deficiency ¹²⁵. Homocysteine levels are elevated in folate deficiency, vitamin B6 deficiency, and patients with hypothyroidism ³⁸. MMA level can be falsely elevated in patients with bacterial overgrowth, especially when there are blind loops of the bowel (following gastric surgery) ¹²⁵. Both levels can be falsely elevated in patients with renal failure ¹²⁵, ³⁸.

Serum holotranscobalamin (holoTC) level measures the metabolically active fraction of serum vitamin B12 and is considered a more accurate test for detecting B12 deficiency ³⁸. Transcobalamin is a transport protein that binds only 10 to 30% of the total plasma B12; however, this constitutes all of the “active fraction” used for metabolic activity ¹²⁵. Limitations of this test include a large window with indeterminate values ¹³⁸. In addition, according to one study, approximately 63% of patients with low holoTC levels had normal methylmalonic acid levels, raising concerns regarding the utility of this test as a true measure of B12 deficiency ¹³⁸. A 2013 study measuring the utility of biomarkers for B12 deficiency compared serum B12 levels to holotranscobalamin and recommended holotranscobalamin as the initial screening test for the detection of B12 deficiency, followed by MMA levels ¹³⁹. They also suggested that an indeterminate holotranscobalamin level between 23 and 75 pmol should be followed by methylmalonic acid testing. Of note, this study was conducted in patients with normal renal function.

Definitive Testing for Pernicious Anemia

Traditionally, vitamin B12 absorption was measured using the Schilling test. This test is now considered obsolete, and there is no available assay for detecting B12 absorption at this time ¹²⁵. In the absence of reliable B12 absorption assays, definitive testing for pernicious anemia relies on the detection of circulating antibodies to intrinsic factors (IFA) and gastric parietal cells (PCA).

Demonstration of circulating intrinsic factor autoantibodies is almost diagnostic of type A (autoimmune) gastritis and pernicious anemia. Intrinsic factor (IF) antibodies are specific for this disorder and can be used to confirm the diagnosis ¹²⁵. There are two types of IF antibodies (IFA). Type 1 IF antibodies block binding of vitamin B12 to intrinsic factor and are found in 70% to 90% of patients with pernicious anemia. Type 2 IF antibodies prevent attachment of the vitamin B12–IF complex to ileal receptors and are present in approximately 35% to 50% of patients with pernicious anemia; they rarely occur in the absence of type 1 IF antibodies. Both type 1 and type 2 antibodies are detected more often in gastric juice than in the serum ¹⁴⁰.

In one case report, the presence of antibodies to intrinsic factors (IFA) was used to diagnose vitamin B12 deficiency in a patient with severe leukoencephalopathy ¹⁴¹. Interestingly, serum vitamin B12, homocysteine, and methylmalonic acid levels were normal. The patient responded to intensive cobalamin therapy ¹⁴¹.

Parietal cell antibodies occurs in 90% of patients with pernicious anemia. However, antibodies to parietal cells (PCA) are not specific for pernicious anemia ¹¹⁶. Some experts advise against routine testing for antibodies to parietal cells (PCA); others recommend routine testing with anti-IF antibodies (IFA) because the combined sensitivity for pernicious anemia approaches 73% ⁹⁴, ³⁸. Dual testing for intrinsic factors antibodies (IFA) and parietal cell antibodies (PCA) with proof of atrophic gastritis is 100% specific for pernicious anemia ¹¹⁶.

In ambiguous cases, a bone marrow biopsy showing megaloblastic erythropoiesis and arrested maturation of myeloid precursor cells will establish the diagnosis ⁹⁴. An alternative approach in difficult cases is to establish the presence of atrophic gastritis with endoscopic evaluation and biopsy and/or showing the presence of hypergastrinemia ⁹⁴. In rare situations, an empiric trial of vitamin B12 replacement can be used to make the diagnosis ⁹⁴. In this scenario, a rise in the reticulocyte count (which occurs within 5 to 14 days) confirms the diagnosis.

Alternative and new approaches to the diagnosis of pernicious anemia are under evaluation. One of these is a newer cobalamin absorption test, which has its basis in measuring the change in serum holotranscobalamin following oral ingestion of non-radiolabeled cobalamin. Another approach has been described using accelerator mass spectrometry to quantify 14C in the blood following an orally administered dose of [14C]-cyanocobalamin ¹²⁵. Recently an ELISA test measuring serum concentration of human IF has been developed and may prove to be an alternate measure of impaired IF production/absorption ¹⁴².

Once the diagnosis of pernicious anemia is established, confirmatory testing with gastroscopy and histologic assessment of the gastric mucosa to assess for the presence of atrophic gastritis is indicated ⁹⁵. Pernicious anemia is recognized as a late-stage complication of autoimmune gastritis, with an increased risk of gastric cancers in this population ⁹⁵. Therefore, a new diagnosis of pernicious anemia warrants endoscopy with biopsies to detect the presence of atrophic gastritis and to rule out gastric cancers ¹³³. The presence of intestinal metaplasia on gastric biopsy confers a diagnosis of atrophic gastritis ¹³³. Pale gastric mucosa and increased visibility of vasculature are typical endoscopic features of atrophic gastritis. With metaplasia, light-blue crests and white opaque fields are present ¹³³.

Recent advances in endoscopic techniques have led to the development of an endoscopic grading of gastric intestinal metaplasia (EGGIM) using noninvasive techniques to assess the presence of metaplasia during endoscopy without any need for biopsies. This system has shown acceptable sensitivity and specificity compared to biopsies and can be used when evaluating patients with pernicious anemia ⁹⁵. In a cross-sectional study of 210 patients with atrophic gastritis, endoscopic grading of gastric intestinal metaplasia (EGGIM) was found to reliably identify more than 90% of patients with gastric corpus intestinal metaplasia. This method was shown to overestimate intestinal metaplasia when pseudopyloric metaplasia was present ⁹⁵.

Additional testing

Testing for iron deficiency is indicated for all patients with pernicious anemia ⁹⁵. Up to 20% of the patients with pernicious anemia have concomitant iron deficiency anemia and, in severe cases, may have microcytic red blood cells ⁹⁴. Serum levels of iron, transferrin, and ferritin should be measured in patients with pernicious anemia, especially when macrocytosis is not present. It is important to remember that patients with pernicious anemia and associated megaloblastic anemia may also develop severe thrombocytopenia ¹²⁵. Platelet production can be reduced by around 10%, and patients may also have abnormal platelet function ¹²⁵. Leukopenia may be present but rarely causes any clinical issues ¹²⁵. Indirect bilirubin and lactate dehydrogenase levels are usually elevated due to the rapid breakdown of red blood cells and intramedullary hemolysis. It is imperative to remember that vitamin B12 and folate levels should be tested simultaneously in patients with macrocytic anemia to ensure both deficiencies are diagnosed if present ³⁸.

Pernicious anemia treatment

Doctors treat pernicious anemia by replacing the missing vitamin B12 in the body. People who have pernicious anemia will need lifelong vitamin B12 treatment ³⁸. Lifelong treatment for patients with confirmed pernicious anemia starts with an intramuscular (IM) injection of 1000 micrograms of B12 (hydroxocobalamin in Europe or cyanocobalamin in the United States) administered daily or every other day for 1 to 2 weeks, followed by weekly injections for 1 to 2 months, then a monthly injection (cyanocobalamin) or every 2 to 3 months (hydroxocobalamin) ³³, ²⁰, ⁹, ¹⁴³, ⁷⁸, ¹⁴⁴.

An alternate approach is an initial dose of 1000 mcg IM injection every other day for 1 to 2 weeks, followed by weekly injections for one month and then monthly injections thereafter ¹²⁵. Response should be monitored by reticulocyte counts, lactic dehydrogenase (LDH), and an appropriate rise in hemoglobin levels. LDH levels decrease and hemoglobin levels increase by about 1 g/dL/week. A rise in LDH might indicate a relapse.

Following the initial intensive treatment phase, patients can continue IM injections, or they can be offered high-dose oral vitamin B12 supplementation for the lifelong maintenance phase. In a 2016 review of oral vitamin B12 replacement for treating pernicious anemia, the authors concluded that “oral vitamin B12 is an effective alternative to vitamin B12 IM injections” ¹⁴⁵. High-dose cyanocobalamin (1000–2000 micrograms) is most commonly taken daily as an oral tablet. Alternate formulations include sublingual and intranasal, but they are not routinely recommended ³³, ²⁰, ⁹, ¹⁴³.

Recent data have suggested that high-dose oral replacement is as effective as IM replacement because passive absorption of vitamin B12 can occur in the absence of intrinsic factor (IF) ¹⁴⁶. Even with a total absence of intrinsic factor (IF), about 1% of an oral dose is absorbed, and the daily requirement for vitamin B12 is 1 µg/day. A study by Zhang and colleagues ¹⁴⁷ found evidence that using orally ingested soy protein isolate (SPI) nanoparticles as a carrier can improve the intestinal transport and absorption of vitamin B12. A 2018 Cochrane review reported oral route was as effective as IM vitamin B12 replacement; however, this was supported by very low-quality evidence ²³. Therefore, current guidelines advise against the use of oral replacement in the initial phase of treatment ³⁸. High-dose oral replacement (with 1000 to 2000 mcg of vitamin B12 daily) can be considered in patients with pernicious anemia for maintenance therapy ³⁸.

The oral route may be necessary in the rare patients who have allergic reactions to parenteral administration, or in patients receiving anticoagulant or antiplatelet agent therapy, in whom intramuscular injections are contraindicated ¹⁴⁸. If the oral route is used, obtain serum cobalamin measurements at periodic intervals to ensure that adequate quantities of cobalamin have been absorbed. Oral cobalamin therapy should not be used in patients with neurologic symptoms ³⁸.

A randomized, placebo-controlled trial of oral cobalamin therapy in 50 patients with borderline serum vitamin B12 levels (125-200 pg/mL) and nonspecific symptoms compatible with subtle vitamin B12 deficiency found that after 1 month, serum methylmalonic acid (MMA) levels were corrected more often in patients receiving oral cobalamin than in those receiving placebo. However, the benefit to the MMA level disappeared after 3 additional months without cobalamin therapy ¹⁴⁹.

A study found that oral cobalamine was more effective than parenteral therapy in some circumstances ¹⁴⁹.

The earliest sign of treatment response is an increase in reticulocyte count that occurs within 5 to 14 days of treatment ⁹⁴. A decrease in methylmalonic acid (MMA) and plasma homocysteine levels has also been observed in the first five days of treatment. Sustained normalization of serum cobalamin subsequently follows. Neuropsychiatric symptoms take a longer time to recover. As noted before, some neurologic symptoms may be irreversible.

Alternate formulations of vitamin B12 have been approved and include sublingual and intranasal formulations. However, data regarding their clinical efficacy is still limited, and they are not routinely recommended.

Patients whose vitamin B12 deficiency is due to underlying diseases involving the intestine or pancreas may require additional therapy ¹⁵⁰. Examples of additional therapy are surgical correction of anatomic abnormalities of the gut that produce small bowel bacterial overgrowth, or the treatment of fish tapeworm anemia or pancreatitis. Elderly patients who also have hypokalemia should receive oral potassium supplements, to prevent severe hypokalemia and possible arrhythmias.

Blood transfusions are rarely required in patients with a megaloblastic anemia that is due to vitamin B12 deficiency ¹⁵¹. The likelihood of obtaining a dramatic response to cobalamin therapy within a few days of initiating treatment makes it unnecessary to subject the patient to the hazards of blood transfusion. Usually, mild-to-moderate congestive heart failure secondary to anemia abates with bed rest and low-dosage diuretic therapy. However, if the congestive heart failure is severe or the patient has coronary insufficiency, transfusion of packed red blood cells may be necessary ¹⁵¹. Transfuse the blood slowly because patients who are transfused for severe anemia often develop circulatory overload. For this reason, low-dose diuretic therapy is often employed with the blood transfusion ¹⁵¹.

Management Guidelines

British Society of Gastroenterology (2019): “We suggest that a baseline endoscopy with biopsies should be considered in individuals aged ≥50 years, with laboratory evidence of pernicious anemia, defined by vitamin B12 deficiency and either positive gastric parietal cell or intrinsic factor antibodies. As gastric adenocarcinoma affects the corpus in pernicious anemia, biopsies should be taken from the greater and lesser curves (evidence level: low quality; grade of recommendation: weak; level of agreement: 93%)” ¹⁵².

European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) (2019): “Patients with autoimmune gastritis (includes those with pernicious anemia) may benefit from endoscopic follow-up every 3 to 5 years. Low-quality evidence, weak recommendation (82% agree [76% strongly or moderately agree])” ¹⁵³.

American Gastroenterological Association (2021): “Providers should recognize pernicious anemia as a late-stage manifestation of autoimmune gastritis that is characterized by vitamin B-12 deficiency and macrocytic anemia. Patients with a new diagnosis of pernicious anemia who have not had a recent endoscopy should undergo endoscopy with topographical biopsies to confirm corpus-predominant atrophic gastritis for risk stratification and to rule out prevalent gastric neoplasia, including neuroendocrine tumors” ¹³³.

Endoscopic Follow-Up

Due to the risk of developing gastric cancer and type 1 gastric neuroendocrine tumors, endoscopic surveillance is the mainstay of the follow-up in pernicious anemia, as the early detection of neoplastic lesions at follow-up could permit a curative resection. European guidelines ¹⁵⁴ suggest a 3-year follow-up in patients with metaplastic atrophic gastritis only in the antrum or only in the corpus, if risk factors, namely autoimmune gastritis, first-degree family history of gastric cancer, incomplete intestinal metaplasia, or persistent H. pylori infection, are present. In case of atrophic gastritis or intestinal metaplasia involving both antrum and corpus, a 3-year follow-up is recommended unless a first-degree family history is present. In this case, endoscopy should be performed every 1–2 years. The 3-year follow-up was shown to be cost-effective in intermediate-risk gastric cancer countries ¹⁵⁵ and was confirmed in another Italian cost-effective study ¹⁵⁶. However, only a few studies were performed to investigate the best interval to follow-up patients harboring this condition. In two studies conducted proposing a 2-year interval, the development of neoplastic lesions was present earlier than the 3-year interval ¹⁵⁷, ¹⁵⁸. However, other studies showed that even in patients with non-extensive atrophic gastritis, namely OLGA I-II/OLGIM I-II, neoplastic lesions could develop ¹⁵⁹, ¹⁶⁰, ¹⁶¹, ¹⁶². Furthermore, a recent longitudinal cohort study, conducted on 122 patients with AAG and 38 patients with multifocal atrophic gastritis in a follow-up program with a 3-year interval, showed the presence of 16 gastric neoplastic lesions at follow-up: 18.7% gastric cancers, 25.0% low-grade dysplasia, 12.5% low-grade dysplasia adenomas and 43.7% type-1 neuroendocrine tumors ¹⁶³. All the diagnosed lesions were endoscopically (87.5%) or surgically (12.5%) treated with favorable outcomes ¹⁶³.

The management of type 1 neuroendocrine tumors and resection strategy have still not been clarified ¹⁶⁴. The European Neuroendocrine Tumor Society guidelines suggest removing tumors larger than 10 mm as they represent neuroendocrine tumors with potentially more aggressive behavior ¹⁶⁵. In a recent prospective study conducted on 80 patients presenting 127 gastric type 1 neuroendocrine tumors, the authors concluded that resection strategy could be planned based on the tumor size. Neuroendocrine tumors smaller than 5 mm could be surveilled, and could be removed by cold snare polypectomy when the size was between 5 and 10 mm and by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) when bigger than 10 mm, even if with low evidence ¹⁶⁶.

European guidelines suggest that surveillance in patients with gastric precancerous conditions should be performed with high-definition electronic chromoendoscopy to better recognize areas at risk for gastric cancer and to perform gastric biopsies. Three meta-analyses showed the high accuracy of conventional and virtual chromoendoscopy for the diagnosis of early gastric cancer and dysplasia in patients harboring precancerous conditions ¹⁶⁷, ¹⁶⁸, ¹⁶⁹. Moreover, in pilot studies, virtual chromoendoscopy seemed to be useful for the characterization of type-1 neuroendocrine tumors ¹⁷⁰.

Pernicious anemia prognosis

Most people with pernicious anemia do well with treatment, except for patients diagnosed with subacute combined degeneration (SCD) ¹⁷¹. It is important to start treatment early. Nerve damage can be permanent if treatment does not start within 6 months of symptoms. Although B12 supplementation stops progression and improves neurologic deficits in most patients with subacute combined degeneration, evidence shows complete resolution only occurs in a small percentage of them ¹⁷². A 2006 observational study evaluating 57 patients with subacute combined degeneration reported only 14% clinical resolution after B12 treatment ¹⁷². Still, the study reported that of these patients, 86% had at least some clinical improvement. Subgroup analysis revealed that the absence of sensory dermatomal deficit, negative Romberg and Babinski signs, age less than 50 years, and less than or equal to 7-segment involvement on magnetic resonance imaging correlated with complete resolution of neurologic symptoms ¹⁷². This study highlights the importance of early diagnosis and treatment of vitamin B12 deficiency, as patients with severe or prolonged neurological symptoms tend to have persistent symptoms despite treatment.

After treatment initiation for pernicious anemia, reticulocytosis begins approximately 5 days later, followed by red blood cell count normalization within 4 to 6 weeks ³³. Typically, neurological symptom improvement is slower than hematological improvement, and the degree of neurological recovery is inversely proportional to the severity and duration of symptoms before treatment. Psychiatric symptoms such as emotional lability and psychosis may rapidly improve ¹⁷³.

With ongoing care and proper treatment, most people who have pernicious anemia can recover, feel well, and live normal lives.

Without treatment, pernicious anemia can lead to serious problems with the heart, nerves, and other parts of the body. Some of these problems may be permanent.

Although vitamin B12 therapy resolves the anemia, it will not cure atrophic gastritis, and patients with pernicious anemia remain at higher risk of gastric cancers throughout their life ¹⁰⁵. There is an increased risk of gastric adenocarcinoma in these patients ¹³³. A longitudinal study from China reported that patients with pernicious anemia and anti-IF or anti-parietal cell antibodies had an unsatisfactory neurologic response to treatment and, over time, developed newly diagnosed hypothyroidism as well as alimentary canal malignancies ¹⁷⁴. Twenty percent of the cancers noted in this study were gastric cancers. This study reported a mean survival of 64 months for patients who developed a malignancy compared to 129 months for those without malignancy. The mortality rate was reported as 31%, with cancer-related deaths representing 37%. Interestingly, the authors reported a higher risk of cancer in patients who were positive for anti-IF antibodies compared to those without these antibodies ¹⁷⁴.

Vitamin B12 deficiency causes

Vitamin B-12 deficiency can result from:

Inadequate intake
Inadequate absorption
Decreased utilization
Use of certain drugs

Inadequate vitamin B12 intake is possible in general malnutrition, chronic alcohol abuse, and vegan or strict vegetarian diets but is otherwise unlikely. Breastfed babies of vegan mothers may develop vitamin B12 deficiency by age 4 to 6 months because in these babies, liver stores (which are normally extensive in other babies) are limited and their rapid growth rate results in high demand. Vitamin B12 malabsorption and deficiency due to inadequate dietary intake are common in the elderly. In the elderly, inadequate absorption most commonly results from decreased acid secretion in the stomach. In such cases, crystalline vitamin B-12 (such as that available in vitamin supplements) can be absorbed, but food-bound vitamin B12 is not liberated and absorbed normally.

Inadequate Vitamin B-12 absorption is the most common cause of vitamin B12 deficiency ¹⁷⁵. Absorption of vitamin B12 from food requires normal function of the stomach, pancreas, and small intestine. Stomach acid and enzymes free vitamin B12 from food, allowing it to bind to R-protein (also known as transcobalamin-1 or haptocorrin), found in saliva and gastric fluids. In the alkaline environment of the small intestine, R-proteins are degraded by pancreatic enzymes, freeing vitamin B12 to bind to intrinsic factor (IF), a protein secreted by specialized cells in the stomach. Receptors on the surface of the ileum (final part of the small intestine) take up the IF-B12 complex only in the presence of calcium, which is supplied by the pancreas ¹⁷⁵. Vitamin B12 can also be absorbed by passive diffusion, but this process is very inefficient—only about 1% absorption of the vitamin B12 dose is absorbed passively ⁵². The prevalent causes of vitamin B12 deficiency are (1) an autoimmune condition known as pernicious anemia, and (2) a disorder called food-bound vitamin B12 malabsorption. Both conditions have been associated with a chronic inflammatory disease of the stomach known as atrophic gastritis. Atrophic gastritis (an autoimmune disease characterized by the presence of antibodies directed against gastric parietal cells and intrinsic factor [IF]). Immune-mediated destruction of gastric parietal cells, gastric mucosal atrophy, hypochlorhydria, decreased IF production, subsequent vitamin B12 malabsorption, vitamin B12 deficiency and pernicious anemia (a type of megaloblastic anemia)

Inadequate absorption may occur in blind loop syndrome (with overgrowth of bacteria) or fish tapeworm infestation; in these cases, bacteria or parasites use ingested vitamin B12 so that less is available for absorption.

Bacterial overgrowth syndromes, ileal resection or gastrointestinal diseases such as terminal ileitis, celiac disease, inflammatory bowel disease, Crohn’s disease and tropical sprue Altered absorption of the IF-vitamin B12 complex in the terminal ileum; intestinal villous atrophy and mucosal injury (celiac disease, Crohn’s disease and tropical sprue) ¹⁷⁶
Intestinal parasitic infestations (often accompanied by eosinophilia) caused by the protozoan Giardia lamblia or the fish tapeworm Diphyllobothrium latum ¹⁷⁶. Vitamin B12 malabsorption through vitamin B12 trapping by the parasites

Vitamin B12 absorption may be inadequate if ileal absorptive sites are destroyed by inflammatory bowel disease or are surgically removed.

Disorders of the exocrine pancreas or pancreatectomy. Insufficient pancreatic enzyme activity leads to a reduction in the proteolytic degradation of haptocorrin (mediated by pancreatic proteases in the small intestine); as a consequence, vitamin B12 remains bound to haptocorrin, cannot form the IF-vitamin B12 complex and is not available for absorption by the enterocytes in the distal ileum ¹⁷⁶.

Less common causes of inadequate vitamin B12 absorption include chronic pancreatitis, gastric bypass, partial or complete gastrectomy, gastric reduction, weight loss surgery and chronic gastritis due to Helicobacter pylori infection, malabsorption syndromes, AIDS, use of certain drugs (eg, antacids, metformin), repeated exposure to nitrous oxide (N2O), and a genetic disorder causing malabsorption in the ileum (Imerslund-Graesbeck syndrome).

Long-term use (≥ 12 months) of drugs altering gastric acid secretion or gastric pH (e.g., proton-pump inhibitors, H2 receptor blockers and antacids) cause vitamin B-12 deficiency. These drugs reduce the production of hydrochloric acid by gastric parietal cells; as a consequence, vitamin B12 is not adequately released from the food matrix due to insufficient hydrochloric acid and low pepsin activity.
The underlying mechanism accounting for metformin-induced vitamin B12 deficiency is not fully understood, although it may involve one or more of the following ¹⁷⁶:
- Interference with the calcium-dependent binding of the IF-vitamin B12 complex to the cubilin receptor on enterocytes at the ileum level;
- Interaction with the cubilin endocytic receptor;
- Alteration in small intestine motility leading to small intestinal bacterial overgrowth and subsequent inhibition of IF-vitamin B12 complex absorption in the distal ileum;
- Alteration in bile acid metabolism and reabsorption;
- Increased liver accumulation of vitamin B12; and (6) Reduced IF secretion by gastric parietal cells.
According to the British Society for Haematology guidelines for diagnosis and treatment of vitamin B12 deficiency, no recommendations can be currently given on prophylactic administration with oral vitamin B12 in patients using metformin ¹⁴³. Despite the lack of definitive guidelines or recommendations on treatment of metformin-induced vitamin B12 deficiency, patients using metformin with concomitant vitamin B12 deficiency should receive cobalamin supplementation aimed to correct this deficiency and prevent the related risk of peripheral nerve damage and/or other clinical consequences ¹⁷⁶. Importantly, prompt vitamin B12 administration should be considered, particularly in metformin-treated patients with vitamin B12 deficiency accompanied by neurologic and/or hematologic manifestations such as peripheral neuropathy and megaloblastic anemia.
Nitrous oxide anesthesia or recreational use of nitrous oxide. Irreversible oxidation and inactivation of the coenzyme form of vitamin B12 (methylcobalamin) at the active site of the vitamin B12-dependent methionine synthase reaction, resulting in increased levels of MMA and homocysteine

Less commonly, decreased utilization of vitamin B12 or use of medications that affect vitamin B12 absorption or metabolism including the bile acid resin cholestyramine (used to treat hypercholesterolemia), colchicine (used for acute gout) and many antibiotics such as neomycin and the anti-tuberculosis drug para-aminosalicylic acid. Unlike long-term use of proton-pump inhibitors, histamine H2-receptor antagonists or metformin, the frequency or duration of use of these drugs is usually insufficient to result in clinical vitamin B12 deficiency ¹⁷⁶. Cholestyramine can chelate IF; colchicine and antibiotics can inhibit endocytosis of the IF-vitamin B12 complex.

Lastly, inherited disorders affecting the sequential steps in the assimilation, transport and intracellular processing and metabolism of vitamin B12 (Imerslund-Gräsbeck syndrome). Reduced expression, binding activity or affinity of receptors and proteins involved in transport, intracellular processing and metabolism of vitamin B12.

Known risk factors for vitamin B12 deficiency include ¹⁷⁷:

Age older than 75 years
Strict vegetarianism or a plant-based diet
Alcohol abuse
Atrophic gastritis
Crohn’s disease
Ileal resection
Pernicious anemia
Postgastrectomy syndrome
Tapeworm infection
Transcobalamin 2 deficiency

Atrophic gastritis

Atrophic gastritis is a histopathologic entity characterized by chronic inflammation of the gastric mucosa with loss of the gastric glandular cells and replacement by intestinal-type epithelium, pyloric-type glands, and fibrous tissue as a response to chronic injury ¹⁷⁸. Atrophy of the gastric mucosa is the endpoint of chronic processes, such as chronic gastritis associated with Helicobacter pylori infection, other unidentified environmental factors, and autoimmunity directed against gastric glandular cells (autoimmune gastritis) ¹⁷⁸. Atrophic gastritis represents the end stage of chronic gastritis, both infectious and autoimmune. In both cases, the clinical manifestations of atrophic gastritis are those of chronic gastritis, but pernicious anemia is observed specifically in patients with autoimmune gastritis and not in those with Helicobacter pylori–associated atrophic gastritis.

Atrophic gastritis is thought to affect 10%-30% of people over 60 years of age ¹⁷⁹. Atrophic gastritis is frequently associated with the presence of autoantibodies directed toward stomach cells (see pernicious anemia) and/or infection by the bacteria, Helicobacter pylori (H. pylori) ¹⁸⁰. Helicobacter pylori (H. pylori) infection induces chronic inflammation of the stomach, which may progress to peptic ulcer disease, atrophic gastritis, and/or gastric cancer in some individuals ¹⁸¹. Diminished gastric function in individuals with atrophic gastritis can result in bacterial overgrowth in the small intestine and cause food-bound vitamin B12 malabsorption. Vitamin B12 levels in serum, plasma, and gastric fluids are significantly decreased in individuals with H. pylori infection, and eradication of the bacteria has been shown to significantly improve vitamin B12 serum concentrations ¹⁸².

Pernicious anemia

Pernicious anemia has been estimated to be present in approximately 2% of individuals over 60 years of age ¹⁰⁸. Although anemia is often a symptom, pernicious anemia is actually the end stage of an autoimmune inflammation of the stomach known as autoimmune atrophic gastritis, resulting in destruction of stomach cells by one’s own antibodies (autoantibodies). Progressive destruction of the cells that line the stomach causes decreased secretion of acid and enzymes required to release food-bound vitamin B12. Antibodies to intrinsic factor (IF) bind to IF preventing formation of the IF-B12 complex, further inhibiting vitamin B12 absorption. About 20% of the relatives of pernicious anemia patients also have the condition, suggesting a genetic predisposition. It is also thought that H. pylori infection could be involved in initiating the autoimmune response in a subset of individuals ¹⁰⁹. Furthermore, co-occurrence of autoimmune atrophic gastritis with other autoimmune conditions, especially autoimmune thyroiditis and type 1 diabetes mellitus, has been reported ¹⁸³, ¹¹⁰.

Treatment of pernicious anemia generally requires injections of vitamin B12 to bypass intestinal absorption. High-dose oral supplementation is another treatment option, because consuming 1,000 μg (1 mg)/day of vitamin B12 orally should result in the absorption of about 10 μg/day (1% of dose) by passive diffusion. In fact, high-dose oral therapy is considered to be as effective as intramuscular injection ⁹.

Food-bound vitamin B12 malabsorption

Food-bound vitamin B12 malabsorption is defined as an impaired ability to absorb food- or protein-bound vitamin B12; individuals with this condition can fully absorb the free form ¹⁸⁴. While the condition is the major cause of poor vitamin B12 status in the elderly population, it is usually associated with atrophic gastritis, a chronic inflammation of the lining of the stomach that ultimately results in the loss of glands in the stomach (atrophy) and decreased stomach acid production (see atrophic gastritis). Because stomach acid is required for the release of vitamin B12 from the proteins in food, vitamin B12 absorption is diminished. Decreased stomach acid production also provides an environment conducive to the overgrowth of anaerobic bacteria in the stomach, which further interferes with vitamin B12 absorption ⁶⁶. Because vitamin B12 in supplements is not bound to protein, and because intrinsic factor (IF) is still available, the absorption of supplemental vitamin B12 is not reduced as it is in pernicious anemia. Thus, individuals with food-bound vitamin B12 malabsorption do not have an increased requirement for vitamin B12; they simply need it in the crystalline form found in fortified foods and dietary supplements.

Inherited disorders of vitamin B12 absorption

Rare cases of inborn errors of vitamin B12 metabolism have been reported in the literature ¹⁷⁵. Imerslund-Gräsbeck syndrome is an inherited vitamin B12 malabsorption syndrome that causes megaloblastic anemia and neurologic disorders of variable severity in affected subjects. Similar clinical symptoms are found in individuals with hereditary IF deficiency (also called congenital pernicious anemia) in whom the lack of IF results in the defective absorption of vitamin B12. Additionally, mutations affecting vitamin B12 transport in the body have been identified ¹⁸⁵.

Other causes of vitamin B12 deficiency

Other causes of vitamin B12 deficiency include surgical resection of the stomach or portions of the small intestine where receptors for the IF-B12 complex are located. Conditions affecting the small intestine, such as malabsorption syndromes (celiac disease and tropical sprue), may also result in vitamin B12 deficiency. Because the pancreas provides critical enzymes, as well as calcium required for vitamin B12 absorption, pancreatic insufficiency may contribute to vitamin B12 deficiency. Since vitamin B12 is found only in foods of animal origin, a strict vegetarian (vegan) diet has resulted in cases of vitamin B12 deficiency. Moreover, alcoholics may experience reduced intestinal absorption of vitamin B12 ⁵² and individuals with acquired immunodeficiency syndrome (AIDS) appear to be at increased risk of deficiency, possibly related to a failure of the IF-B12 receptor to take up the IF-B12 complex ⁶⁶. Furthermore, long-term use of acid-reducing drugs has also been implicated in vitamin B12 deficiency (see drug interactions below).

Drug interactions

A number of drugs reduce the absorption of vitamin B12. Proton-pump inhibitors (e.g., omeprazole and lansoprazole), used for therapy of Zollinger-Ellison syndrome and gastroesophageal reflux disease (GERD), markedly decrease stomach acid secretion required for the release of vitamin B12 from food but not from supplements ⁴⁶. Long-term use of proton-pump inhibitors has been found to decrease blood vitamin B12 levels. However, vitamin B12 deficiency does not generally develop until after at least three years of continuous therapy ¹⁸⁶, ¹⁸⁷. Another class of gastric acid inhibitors known as histamine2 (H2)-receptor antagonists (e.g., cimetidine, famotidine, and ranitidine), often used to treat peptic ulcer disease, has also been found to decrease the absorption of vitamin B12 from food ⁴⁶. It is not clear whether the long-term use of H2-receptor antagonists could cause overt vitamin B12 deficiency ¹⁸⁸, ¹⁸⁹. Individuals taking drugs that inhibit gastric acid secretion should consider taking vitamin B12 in the form of a supplement because gastric acid is not required for its absorption.

Other drugs found to inhibit vitamin B12 absorption from food include cholestyramine (a bile acid-binding resin used in the treatment of high cholesterol), chloramphenicol and neomycin (antibiotics), and colchicine (medicine for gout treatment) ⁴⁶. Metformin, a medication for individuals with type 2 diabetes, was found to decrease vitamin B12 absorption by tying up free calcium required for absorption of the IF-B12 complex ¹⁷⁶, ¹⁹⁰. However, the clinical significance of this is unclear ¹⁹¹. It is not known whether calcium supplementation can reverse vitamin B12 malabsorption; therefore, calcium supplementation is not currently prescribed for the prevention or treatment of metformin-induced vitamin B12 deficiency ¹⁹². Previous reports that megadoses of vitamin C destroy vitamin B12 have not been supported ¹⁹³ and may have been an artifact of the assay used to measure vitamin B12 levels ⁴⁶.

Nitrous oxide, a commonly used anesthetic, oxidizes and inactivates vitamin B12, thus inhibiting both of the vitamin B12-dependent enzymes, and can produce many of the clinical features of vitamin B12 deficiency, such as megaloblastic anemia or neuropathy ⁴⁶. Since nitrous oxide is commonly used for surgery in the elderly and in childbirth, some experts feel vitamin B12 deficiency should be ruled out prior to its use ¹⁷⁹, ¹⁹⁴.

Large doses of folic acid given to an individual with an undiagnosed vitamin B12 deficiency could correct megaloblastic anemia without correcting the underlying vitamin B12 deficiency, leaving the individual at risk of developing irreversible neurologic damage ⁴⁶. For this reason, the Food and Nutrition Board of the US Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1,000 mcg (1 mg) daily ¹⁹⁵.

Groups at risk of vitamin B12 deficiency

The main causes of Vitamin B-12 deficiency include Vitamin B-12 malabsorption from food, pernicious anemia, postsurgical malabsorption, and dietary deficiency ¹⁹⁶. However, in many cases, the cause of Vitamin B-12 deficiency is unknown.

The following groups are among those most likely to be Vitamin B-12 deficient.

Older adults

Individuals with pernicious anemia

Pernicious anemia is an irreversible auto-immune disease that affects the gastric mucosa and results in gastric atrophy ⁷⁸. This disease leads to attacks on parietal cells in the stomach, resulting in failure to produce intrinsic factor (IF) and malabsorption of dietary vitamin B12, recycled biliary vitamin B12, and free vitamin B12 ⁷⁹, ⁶⁰. Therefore, without treatment, pernicious anemia causes vitamin B12 deficiency, even in the presence of adequate vitamin B12 intakes.

Pernicious anemia refers to one of the hematologic manifestations of chronic auto-immune gastritis, in which the immune system targets the parietal cells of the stomach or intrinsic factor itself, leading to decreased absorption of vitamin B12. Asymptomatic autoimmune gastritis likely precedes gastric atrophy by 10 to 20 years, followed by the onset of iron-deficiency anemia that occurs as early as 20 years before vitamin B12 deficiency pernicious anemia.

In rare cases, pernicious anemia is passed down through families. This is called congenital pernicious anemia. Babies with this type of anemia do not make enough intrinsic factor. Or they cannot properly absorb vitamin B12 in the small intestine.

Individuals with gastrointestinal disorders

Individuals who have had gastrointestinal surgery

Vegetarians

Infants of vegan women

Vitamin B12 deficiency prevention

Because of potential interactions from prolonged medication use, healthcare providers should consider screening patients for vitamin B12 deficiency if they have been taking proton pump inhibitors or H2 blockers for more than 12 months, or metformin for more than four months ¹³. The average intake of vitamin B12 in the United States is 3.4 mcg per day, and the recommended dietary allowance is 2.4 mcg per day for adult men and nonpregnant women, and 2.6 mcg per day for pregnant women ⁵¹. Patients older than 50 years may not be able to adequately absorb dietary vitamin B12 and should consume food fortified with vitamin B12 ⁵¹. Vegans and strict vegetarians should consume fortified cereals or supplements to prevent vitamin B12 deficiency. The American Society for Metabolic and Bariatric Surgery recommends that patients who have had weight loss surgery take 1 mg of oral vitamin B12 per day indefinitely ¹⁹⁷.

Vitamin B12 deficiency signs and symptoms

Vitamin B12 deficiency affects multiple systems, and signs and symptoms vary in severity from mild fatigue to severe neurologic impairment ¹³. The substantial liver storage of vitamin B12 can delay signs and symptoms for up to 10 years after the onset of Vitamin B12 deficiency ¹⁹⁸.

The signs and symptoms of vitamin B12 deficiency include ¹⁹⁹:

anaemia resulting from impaired red blood cell production
loss of peripheral nerve function that can result in impaired sensation, movement or organ function
visual disturbance
memory loss
psychiatric abnormalities
temporary infertility in women
vitamin B12 deficiency during pregnancy can result in fetal abnormalities, such as neural tube defects ²⁰⁰, ²⁰¹, ²⁰².

Vitamin B12 deficiency is generally characterized by a specific type of anemia called megaloblastic anemia. Anemia usually develops insidiously. It can cause fatigue (easily fatigued with exertion), palpitations, pale skin, weakness, constipation, loss of appetite, and weight loss ¹², ³³, ³⁴, ¹², ¹⁵. Megaloblastic anemia is often more severe than its symptoms indicate because its slow evolution allowing physiologic adaptation.

Skin hyperpigmentation, glossitis (swollen inflamed tongue) and infertility have also been reported ¹², ³³, ³⁴. Neurologic signs and symptoms are caused by progressive demyelination and can include peripheral neuropathy, absence of normal neurologic reflexes (areflexia), and the loss of proprioception and vibratory sense. Areflexia (absence of normal neurologic reflexes) can be permanent if neuronal death occurs in the posterior and lateral spinal cord tracts ¹², ³³, ³⁴, ²⁰³. Dementia-like disease, including episodes of psychosis, is possible with more severe and chronic vitamin B12 deficiency ¹², ²⁰³. Clinical evaluation seems to show an inverse relationship between the severity of megaloblastic anemia and the degree of neurologic impairment ³³.

Maternal vitamin B12 deficiency during pregnancy or while breastfeeding may lead to neural tube defects, developmental delay, failure to thrive, hypotonia, ataxia, and anemia ³⁰, ²⁰⁴, ²⁰⁵, ²⁰⁶, ²⁰⁷. Women at high risk or with known deficiency should supplement with vitamin B12 during pregnancy or while breastfeeding ³⁰, ²⁰⁴, ²⁰⁵, ²⁰⁶, ²⁰⁷.

Symptoms of vitamin B12 deficiency can take decades to develop, and can usually only be diagnosed by a medical professional ¹², ¹³.

Vitamin B12 deficiency symptoms can include:

Diarrhea or constipation
Nausea
Vomiting
Fatigue, lack of energy, or lightheadedness when standing up or with exertion
Loss of appetite
Pale skin (mild jaundice)
Shortness of breath, mostly during exercise
Heartburn
Swollen, red tongue or bleeding gums

General symptoms of anemia may include:

extreme tiredness (fatigue)
lack of energy (lethargy)
breathlessness
feeling faint
headaches
pale skin
noticeable heartbeats (palpitations)
hearing sounds coming from inside the body, rather than from an outside source (tinnitus)
loss of appetite and weight loss

If you have anemia caused by a vitamin B12 deficiency, you may have other symptoms, such as ³⁰, ²⁰⁸:

a pale yellow tinge to your skin. In advanced anemia, severe pale skin with jaundice (due to hemolysis) produces a “peculiar lemon-yellow” skin color ¹²⁵.
vitiligo
skin hyperpigmentation
a sore and red tongue (glossitis)
mouth ulcers
pins and needles (paresthesia)
changes in the way that you walk and move around (gait abnormalities)
disturbed vision
irritability
depression
changes in the way you think, feel and behave
a decline in your mental abilities, such as memory, understanding and judgement (dementia)
acute psychosis
areflexia
loss of proprioception and vibratory sense
impaired sense of smell

If you have a low vitamin B12 level for a long time, you can have nervous system damage. Symptoms can include ²⁰⁹:

Confusion
Short-term memory loss
Depression
Loss of balance
Numbness and tingling in the hands and feet
Problems concentrating
Irritability
Hallucinations
Delusions
Optic nerve atrophy

Some of these symptoms can also happen in people who have a vitamin B12 deficiency but have not developed anemia.

Anemia usually develops insidiously. It is often more severe than its symptoms indicate because its slow evolution allows physiologic adaptation.

Occasionally, splenomegaly and hepatomegaly occur. Various gastrointestinal symptoms, including weight loss and poorly localized abdominal pain, may occur. Glossitis, usually described as burning of the tongue, is uncommon.

Neurologic symptoms develop independently from and often without hematologic abnormalities.

Subacute combined degeneration refers to degenerative changes in the nervous system due to Vitamin B12 deficiency; they affect mostly brain and spinal cord white matter, including the dorsal columns, the lateral corticospinal tracts, and the spinocerebellar tracts ²¹⁰, ²¹¹. Demyelinating or axonal peripheral neuropathies can occur ²¹², ²¹⁰.

In early stages, decreased position (proprioception) and vibratory sensation in the extremities is accompanied by mild to moderate weakness and hyporeflexia. In later stages, spasticity, extensor plantar responses, greater loss of position and vibratory sensation in the lower extremities, and ataxia emerge ²¹³, ⁴². These deficits may develop in a stocking-glove distribution. Tactile, pain, and temperature sensations are usually spared but may be difficult to assess in the elderly. Areflexia can be permanent if neuronal death occurs in the posterior and lateral spinal cord tracts ²⁰³, ³⁴.

Some patients are also irritable and mildly depressed. Dementia-like disease, including episodes of psychosis, paranoia (megaloblastic madness), poor memory, delirium, depression, confusion, and, at times, postural hypotension may occur in advanced cases ²⁰³, ¹². The confusion may be difficult to differentiate from age-related dementias, such as Alzheimer disease.

Neurologic symptoms may develop independently from and often without hematologic abnormalities. Clinical evaluation seems to show an inverse relationship between the severity of megaloblastic anemia and the degree of neurologic impairment ¹⁵.

Megaloblastic anemia

Diminished activity of methionine synthase in vitamin B12 deficiency inhibits the regeneration of tetrahydrofolate (THF) and traps folate in a form that is not usable by the body, resulting in symptoms of folate deficiency even in the presence of adequate folate levels. Thus, in both folate and vitamin B12 deficiencies, folate is unavailable to participate in DNA synthesis. This impairment of DNA synthesis affects the rapidly dividing cells of the bone marrow earlier than other cells, resulting in the production of large, immature, hemoglobin-poor red blood cells. The resulting anemia is known as megaloblastic anemia and is the symptom for which the disease, pernicious anemia, was named ⁶⁶. Supplementation with folic acid will provide enough usable folate to restore normal red blood cell formation. However, if vitamin B12 deficiency is the cause, it will persist despite the resolution of the anemia. Thus, megaloblastic anemia should not be treated with folic acid until the underlying cause has been determined ²¹⁴.

Neurologic symptoms

The neurologic symptoms of vitamin B12 deficiency include numbness and tingling of the hands and, more commonly, the feet; difficulty walking; memory loss; disorientation; and dementia with or without mood changes. Although the progression of neurologic complications is generally gradual, such symptoms may not be reversed with treatment of vitamin B12 deficiency, especially if they have been present for a long time. The most common initial sign and symptom of vitamin B12 deficiency is burning or prickling sensation that is usually felt in the hands, arms, legs, or feet (paresthesia), present in 70% of patients with neurological symptoms ²¹⁵. Paresthesias are described as tingling or numbness, and, in contrast with other neuropathies, typically start in hands or both distal extremities ²¹⁵, ²¹⁶. Other neurological manifestations may include subacute combined degeneration characterized by lesion of the posterior and lateral columns of the spinal cord leading to asthenia, spasticity, impaired vibratory and proprioceptive sensation with ataxia and extensor plantar responses ²¹⁶; autonomic dysfunction (erectile and bladder dysfunction) ²¹⁷; optic neuropathy with progression to visual loss (characterized by central and centrocecal scotomas) ²¹⁸, and memory and mood involvement, up to dementia ⁹⁵.

Neurologic complications are not always associated with megaloblastic anemia and are the only clinical symptom of vitamin B12 deficiency in about 25% of cases ⁶⁵. Although vitamin B12 deficiency is known to damage the myelin sheath covering cranial, spinal, and peripheral nerves, the biochemical processes leading to neurological damage in vitamin B12 deficiency are not yet fully understood ²¹⁹.

Gastrointestinal symptoms

Tongue soreness, appetite loss, and constipation have also been associated with vitamin B12 deficiency. The origins of these symptoms are unclear, but they may be related to the stomach inflammation underlying some cases of vitamin B12 deficiency and to the progressive destruction of the lining of the stomach ⁶⁵.

Hyperhomocysteinemia

High levels of homocysteine in the blood (hyperhomocysteinemia) has been linked to heart disease and stroke ¹⁰. Hyperhomocysteinemia can be caused by a deficiency of either vitamin B12 or folate, and in human subjects mild (13–24 µM) and moderate (25–60 µM) hyperhomocysteinemia are also associated with mutations of MTHFR genes.

Vitamin B12 deficiency hyperhomocysteinemia may be associated with osteoporosis, depression, cognitive decline, and some forms of dementia in the elderly ¹⁰. More recently, vitamin B12 deficiency has been reported as common among patients with hyperhomocysteinemia and thrombosis ²²⁰, although the presence of a direct effect of vitamin B12 deficiency rather than mediated by hyperhomocysteinemia or other factors is uncertain. In fact, lifestyle-related factors, such as smoking status, body mass index (BMI), and physical activity, could interfere between hyperhomocysteinemia and the thromboembolism relationship ²²¹. Moreover, the effect of lowering homocysteine levels in patients with intermediate (total homocysteine 30–100 µmol/L) or severe hyperhomocysteinemia (total homocysteine > 100 µmol/L) remains unknown ²²². The cases described below report examples of vitamin B12 deficiency and hyperhomocysteinemia related to different causes.

A case of cerebral venous thrombosis secondary to hyperhomocysteinemia caused by vitamin B12 deficiency in a 32-year-old Indo-Aryan man who followed a strict vegetarian diet is reported by Kapur ²²³. The preliminary blood examination revealed macrocytic anemia with hemoglobin of 11.4 g/dL and mean corpuscular volume (MCV) of 110 fL ²²³. Peripheral blood film showed macrocytes and macro-ovalocytes with hypersegmented neutrophils; low serum cobalamin levels 68 pg/mL (200–600) with normal folate levels and total serum homocysteine
levels of 36 μmol/L (5.0–13.9) were observed ²²³. In addition to other treatments, the patient received parenteral cyanocobalamin 1000 μg once daily for seven days. Gradually, he regained sensorium, his power improved, and he was discharged on orally administered sodium valproate, warfarin, and methylcobalamin. Repeated investigations undertaken at six months after stopping anticoagulants showed normal serum cobalamin 364 pg/mL (200–600) and fasting total homocysteine levels 8.4 μmol/L. The authors conclude that hyperhomocysteinemia is an independent risk factor for cerebral venous thrombosis in patients with cobalamin deficiency, especially those who follow a strict vegetarian diet, and that hyperhomocysteinemia can be easily reversed with vitamin supplementation, cobalamin, and folic acid ²²³.

The cases of four Moroccan patients with acute vein thrombosis of different sites are reported by Ammouri ²²⁴. Three men and one woman of different ages (a 34-year-old man, a 60-year-old man, a 58-year-old man, and a 47-year-old woman) were selected. All patients presented low hemoglobin level (from 8.6 g/dL to 9.5 g/dL), low MCV (mean corpuscular volume), low cobalamin plasma level (about 60 pg/mL; normal >120 pg/mL), and high levels of plasma homocysteine (50 to 200 μmol/L; normal range <15 µmol/L) with normal folate plasma levels. For all, pernicious anemia and venous thrombosis secondary to hyperhomocysteinemia were evident. First, the authors speculated that normal folate levels may have contributed to the delay in the diagnosis of pernicious anemia, leading to severe hyperhomocysteinemia and the consequent development of vascular injury ²²⁴.

Hyperhomocysteinemia could lead to venous thrombosis by several pathways. For example, the toxic effect of homocysteine on the vascular endothelium and on the dotting cascade, as well procoagulant properties of homocysteine, including the decrease of antithrombin III binding to endothelial heparan sulfate, an increase of affinity between lipoprotein(a) and fibrin, induction of tissue factor activity in endothelial cells, and inhibition of inactivation of factor V by activated protein. In all patients, clinical and biological abnormalities disappeared upon vitamin B12 supplementation. The authors concluded that vitamin B12 supplements can rapidly correct hyperhomocysteinemia avoiding and preventing thrombotic events ²²⁴.

Tanaka et al. ²²² reported a case of a 39-year-old man with inferior vena cava (IVC) thrombus. The analysis of risk factors of venous thromboembolism shown hyperhomocysteinemia (total homocysteine 83.1 µmol/L; normal range 5–15 µmol/L) due to an unbalanced diet with a deficiency of folic acid and vitamin B12. The patient was treated with both folic acid and vitamin B6/vitamin B12 supplementation in association with warfarin, inducing a significant resolution of thrombus after four weeks and no evidence of recurrent IVC thrombus at six months. The authors concluded that B vitamins and folic acid therapy might be effective in patients with severe hyperhomocysteinemia ²²².

An interesting case of a 43-year-old man presenting with a two-week history of painless ascending sensory disturbances, suspected to be suffering from acute inflammatory polyneuropathy, is reported by Ulrich et al. ²²⁵. On clinical examination, deep tendon reflexes were preserved, muscle strength was 5/5 everywhere, and gait was ataxic. Initial laboratory assessment showed nearly normal holotranscobalamin (43 pmol/L; pmol/L normal >50 pmol/L), suggesting no vitamin B12 deficiency. Surprisingly, further investigation showed high homocysteine (48.5 µmol/L; normal <10 µmol/L), suggesting an impairment of vitamin B12-dependent metabolism leading to the diagnosis of subacute combined degeneration. The patient remembered having taken tablets containing cobalamin for three days before hospitalization. The authors concluded that holotranscobalamin can be rapidly normalized during supplementation and the analysis of methylmalonic acid (MMA) and homocysteine might help to detect B12 deficiency in patients who recently started supplementation.

A case of a 24-year-old male with unprovoked bilateral submassive pulmonary emboli with a high level of homocysteine without anemia is reported by Kovalenko et al. ²²⁶. Complete blood count showed a MCV of 104fL without anemia, and homocysteine level was 41.3 μmol/L (normal 4.0–13.7 μmol/L). Workup for macrocytosis was notable for low vitamin B12 (72 pg/mL) and folate (2.1 ng/mL) levels. After vitamin B12 supplementation, serum homocysteine levels did not decrease to normal values. The authors speculated that a poor absorption of B vitamins due to a small bowel resection two years before and excessive alcohol consumption could have impaired the results. Another case associated with alcoholism was previously described by Goette et al. ²²⁷. The authors described a rare case of a 32-year-old man with severe hyperhomocysteinemia underlying a probable cause of thromboembolic complications ²²⁷. The patient did not have a history of cardiovascular disease, but he had at least a six-month history of alcohol abuse at least six months before hospital admission. Laboratory assays showed abnormalities in liver functions, vitamin B12 (226 pg/mL; normal range 150–675 pg/mL) and folate (1.6 μg/L; normal range 1.4–11.8 μg/L) were low but within normal range, while serum homocysteine was at least 12 times higher than normal (173 μmol/L). The patient was treated with 5 mg oral folic acid and 20 mg oral vitamin B6 daily. Vitamin supplementation was then adapted and integrated with other drugs, such as weight-adapted low molecular weight heparin and L-arginine. For some patients, the authors suggested the screening for hyperhomocysteinemia in association with endothelial dysfunction markers as appropriate ²²⁷.

Elevated plasma homocysteine is involved in cognitive decline, including Alzheimer’s disease, mild cognitive impairment, and dementia, especially in elderly subjects. McCaddon ²²⁸ reported seven cases of older patients (four women aged 78 years, 84 years, 77 years and 87 years, 84 years old, and two men 71 and 75 years old). They presented with cognitive impairment and/or depression and dementia ²²⁸. Each had different vitamin B12 status with hyperhomocysteinemia. Treatment with N-acetylcysteine, together with B vitamin supplements, improves cognitive status in hyperhomocysteinemic patients. The authors concluded that it could be important to evaluate inadequate vitamin B12 and folate metabolism in subjects with cognitive diseases, underlining the importance of clinical trials to evaluate the beneficial effects of a synergistic approach to cognitively impaired hyperhomocysteinaemic patients ²²⁸.

Vitamin B12 deficiency complications

As most cases of vitamin B12 deficiency can be easily and effectively treated, complications are rare. But complications can occasionally develop, particularly if you have been vitamin B12 deficient for some time.

Vitamin B12 deficiency complications can include ²²⁹:

Heart failure due to the anemia
Severe disabling neurological deficits
Risk of gastric cancer
Risk of developing an autoimmune disorder like type 1 diabetes, myasthenia gravis, Hashimoto disease, or rheumatoid arthritis.

Anemia complications

All types of anaemia, regardless of the cause, can lead to heart and lung complications as the heart struggles to pump oxygen to the vital organs. A lack of vitamin B12 with or without anemia can cause complications.

Adults with severe anemia are at risk of developing:

an abnormally fast heartbeat (tachycardia)
heart failure, where the heart fails to pump enough blood around the body at the right pressure

Neurological problems

A lack of vitamin B12 can cause neurological problems, which affect your nervous system, such as:

vision problems
memory loss
pins and needles (paraesthesia)
loss of physical co-ordination (ataxia), which can affect your whole body and cause difficulty speaking or walking
damage to parts of the nervous system (peripheral neuropathy), particularly in the legs

If neurological problems do develop, they may be irreversible.

Stomach cancer

If you have a vitamin B12 deficiency caused by pernicious anemia, a condition where your immune system attacks healthy cells in your stomach, your risk of developing stomach cancer is increased.

Neural tube defects

If you’re pregnant, not having enough vitamin B12 can increase the risk of your baby developing a serious birth defect known as a neural tube defect. The neural tube is a narrow channel that eventually forms the brain and spinal cord.

Examples of neural tube defects include:

Spina bifida – where the baby’s spine does not develop properly
Anencephaly – where a baby is born without parts of the brain and skull
Encephalocele – where a membrane or skin-covered sac containing part of the brain pushes out of a hole in the skull

Infertility

Vitamin B12 deficiency can sometimes lead to temporary infertility, an inability to conceive. Infertility usually improves with appropriate vitamin B12 treatment.

Effects of nitrous oxide

Nitrous oxide (N2O), commonly known as ‘laughing gas’, is a type of anesthetic used in dental treatments and childbirth. Using nitrous oxide can reduce the levels of vitamin B12 in your body. Nitrous oxide oxidizes and inactivates vitamin B12, thus inhibiting both of the vitamin B12-dependent enzymes, and can produce many of the clinical features of vitamin B12 deficiency, such as megaloblastic anemia or neuropathy ⁴⁶. Since nitrous oxide is commonly used for surgery and childbirth, some experts feel vitamin B12 deficiency should be ruled out prior to its use ¹⁹⁴, ¹⁷⁹. If you are pregnant and have vitamin B12 deficiency, discuss with your doctor or midwife whether you will be able to use nitrous oxide during labor.

Vitamin B12 deficiency diagnosis

Your health care provider will perform a physical exam. This may reveal problems with your reflexes. It is important to remember that severe neurologic disease may occur without anemia or macrocytosis. Figure 5 presents an approach to diagnosing vitamin B12 deficiency and pernicious anemia ¹⁴³.

To screen for vitamin B12 deficiency, your doctor may order blood tests to see whether you have low hemoglobin or vitamin B12 levels. Complete blood test checking for anemia and vitamin B-12 and folate levels ³³, ²³⁰, ³⁵, ²³¹. Bone marrow suppression is common and potentially affects all cell lines, with megaloblastic anemia being most common ¹², ³³, ³⁴. The resultant abnormal erythropoiesis can trigger other notable abnormal laboratory findings, such as decreased haptoglobin levels, high lactate dehydrogenase levels, and elevated reticulocyte count ¹², ³³, ³⁴.
Vitamin B12 deficiency results in impairment of the activities of vitamin B12-requiring enzymes. Impaired activity of methionine synthase results in elevated homocysteine levels, while impaired activity of L-methylmalonyl-CoA mutase results in increased levels of a metabolite of methylmalonyl-CoA called methylmalonic acid (MMA). While individuals with mild vitamin B12 deficiency may not experience symptoms, blood levels of homocysteine and/or methylmalonic acid (MMA) may be elevated ¹⁹⁴. The Schilling test, which was once the diagnostic standard for pernicious anemia, is no longer available in the United States.
Patients diagnosed with vitamin B12 deficiency whose history and physical examination do not suggest an obvious dietary or malabsorptive etiology should be tested for pernicious anemia with anti-intrinsic factor antibodies, particularly if other autoimmune disorders are present ¹², ³³, ³⁴, ¹⁴³. Patients with pernicious anemia may have hematologic findings consistent w ith normocytic anemia ¹². If anti-intrinsic factor results are negative but suspicion for pernicious anemia remains, an elevated serum gastrin level is consistent with the diagnosis ³³.

To date, there is no consensus about the exact definition of vitamin B12 deficiency ²³². There is still a significant debate within the scientific community about the specific cut-off values that should be applied to define a low vitamin B12 status and about the definition of the best biomarker or combination of biomarkers to assess vitamin B12 status ²³², ²¹. Varying cut-off values invariably lead to underestimating or overestimating the incidence of vitamin B12 deficiency ¹⁷⁶. With regard to the definition of an optimal vitamin B12 status, a low vitamin B12 status (frank vitamin B12 deficiency) is generally defined as total serum vitamin B12 levels of < 148 pmol/L, with levels between 148 and 221 pmol/L being considered as “borderline” or suggestive of “marginal deficiency” ²⁰.

In light of the above remarks, measurement of functional biomarkers of vitamin B12 status (homocysteine and methylmalonic acid [MMA]) may be useful to confirm the diagnosis of true vitamin B12 deficiency, particularly in the presence of low-normal total serum vitamin B12 levels and/or clinical suspicion of vitamin B12 deficiency ²³². Therefore, total vitamin B12, its bioactive protein-bound form holotranscobalamin (HoloTC), homocysteine and methylmalonic acid (MMA) are the preferred serum biomarkers to accurately assess vitamin B12 status ²¹. However, it is worth noting that serum levels of homocysteine and methylmalonic acid (MMA) can be elevated even in the presence of folate deficiency, which can also be associated with macrocytic anemia and thereby confused with vitamin B12 deficiency ¹⁷⁶. Therefore, measurement of serum folate, MMA and homocysteine levels can help to distinguish vitamin B12 deficiency from folate deficiency. Serum levels of both homocysteine and MMA are often elevated in the presence of true vitamin B12 deficiency. Conversely, homocysteine levels are elevated but MMA levels are normal in the presence of folate deficiency ²³³. Yet, it is also worth remembering that both homocysteine and MMA levels can be elevated in the presence of kidney disease ²³².

Figure 6. Vitamin B12 deficiency diagnosis

Footnote: Suggested approach to the patient with suspected vitamin B12 deficiency.

[Source ¹³ ]

Table 5 lists the relative sensitivities and specificities of various laboratory tests ²³⁴

Table 5. Vitamin B12 deficiency laboratory tests sensitivities and specificities

[Source ¹³ ]

The diagnosis of vitamin B12 deficiency is based mainly on complete blood count and vitamin B-12 and folate levels. Complete blood count usually detects megaloblastic anemia. Tissue deficiency and macrocytic indexes may precede the development of anemia. The diagnosis of vitamin B12 deficiency is based mainly on blood measurements of serum vitamin B12 level less than 200 pg/mL (148 pmol/L), complemented with second‐line tests including total homocysteine and methylmalonic acid levels, which are metabolic indicators of vitamin B12 deficiency ²³⁵. A serum vitamin B12 level less than 150 pg/mL (< 111 pmol/L) is diagnostic for vitamin B-12 deficiency ¹², ³³. Serum vitamin B12 levels may be artificially elevated in patients with alcoholism, liver disease, or cancer because of decreased hepatic clearance of transport proteins and resultant higher circulating levels of vitamin B12; physicians should use caution when interpreting laboratory results in these patients ³⁶, ³⁷. In patients with a normal or low-normal serum vitamin B12 level, complete blood count results demonstrating macrocytosis, or suspected clinical manifestations, a serum methylmalonic acid (MMA) level is an appropriate next step and is a more direct measure of vitamin B12’s physiologic activity ¹⁴³, ³⁴, ¹², ³³. Although not clinically validated or available for widespread use, measurement of holotranscobalamin, the metabolically active form of vitamin B12, is an emerging method of detecting deficiency ¹⁴³.

The folate level is also measured because vitamin B12 deficiency must be differentiated from folate deficiency as a cause of megaloblastic anemia; folate supplementation can mask vitamin B12 deficiency and may alleviate megaloblastic anemia but allow the neurologic deficits to progress or even accelerate.

Studies have indicated that an estimated 20% of people can present with neuropsychiatric symptoms in the absence of hematological abnormalities ²³⁶.

When clinical judgment suggests vitamin B12 deficiency but the vitamin B12 level is low-normal (200 to 350 pg/mL [145 to 260 pmol/L]) or hematologic indexes are normal, other tests can be done. They include measuring the following:

Serum methylmalonic acid (MMA) levels: An elevated MMA level supports vitamin B12 deficiency but may be due to renal failure. Methylmalonic acid (MMA) levels can also be used to monitor the response to treatment. Methylmalonic acid levels remain normal in folate deficiency.
Homocysteine levels: Levels may be elevated with either vitamin B12 or folate deficiency.
Less commonly, holotranscobalamin 2 (transcobalamin 2–B12 complex) content: When holotranscobalamin 2 is < 40 pg/mL (< 30 pmol/L), Vitamin B-12 is deficient.

After Vitamin B-12 deficiency is diagnosed, additional tests (eg, Schilling test) may be indicated for younger adults but usually not for the elderly. Unless dietary Vitamin B-12 is obviously inadequate, serum gastrin levels or autoantibodies to intrinsic factor may be measured; sensitivity and specificity of these tests may be poor.

Schilling test

The Schilling test is useful only if diagnosing intrinsic factor deficiency is important, as in classic pernicious anemia. This test is not necessary for most elderly patients. The Schilling test measures absorption of free radiolabeled Vitamin B-12. Radiolabeled Vitamin B-12 is given orally, followed in 1 to 6 h by 1000 mcg (1 mg) of parenteral Vitamin B-12, which reduces uptake of radiolabeled Vitamin B-12 by the liver. Absorbed radiolabeled Vitamin B-12 is excreted in urine, which is collected for 24 h. The amount excreted is measured, and the percentage of total radiolabeled Vitamin B-12 is determined. If absorption is normal, ≥ 9% of the dose given appears in the urine. Reduced urinary excretion (< 5% if kidney function is normal) indicates inadequate Vitamin B-12 absorption. Improved absorption with the subsequent addition of intrinsic factor to radiolabeled Vitamin B-12 confirms the diagnosis of pernicious anemia.

The test is often difficult to do or interpret because of incomplete urine collection or renal insufficiency. In addition, because the Schilling test does not measure absorption of protein-bound Vitamin B-12, the test does not detect defective liberation of Vitamin B-12 from foods, which is common among the elderly. The Schilling test repletes Vitamin B-12 and can mask deficiency, so it should be done only after all other diagnostic tests and therapeutic trials.

If malabsorption is identified, the Schilling test can be repeated after a 2-wk trial of an oral antibiotic. If antibiotic therapy corrects malabsorption, the likely cause is intestinal overgrowth of bacteria (eg, blind-loop syndrome).

Vitamin B12 deficiency test

Diagnosis of Vitamin B-12 deficiency is based on complete blood count and Vitamin B-12 and folate levels. Complete blood count usually detects megaloblastic anemia. Tissue deficiency and macrocytic indexes may precede the development of anemia. A Vitamin B-12 level < 200 pg/mL (< 145 pmol/L) indicates Vitamin B-12 deficiency. The folate level is measured because Vitamin B-12 deficiency must be differentiated from folate deficiency as a cause of megaloblastic anemia; folate supplementation can mask Vitamin B-12 deficiency and may alleviate megaloblastic anemia but allow the neurologic deficits to progress or even accelerate.

When clinical judgment suggests Vitamin B-12 deficiency but the Vitamin B-12 level is low-normal (200 to 350 pg/mL [145 to 260 pmol/L]) or hematologic indexes are normal, other tests can be done. They include measuring the following:

Serum methylmalonic acid (MMA) levels: An elevated MMA level supports Vitamin B-12 deficiency but may be due to renal failure. Methylmalonic acid (MMA) levels can also be used to monitor the response to treatment. Methylmalonic acid levels remain normal in folate deficiency.
Homocysteine levels: Levels may be elevated with either Vitamin B-12 or folate deficiency.
Less commonly, holotranscobalamin II (transcobalamin II–B12 complex) content: When holotranscobalamin II is < 40 pg/mL (< 30 pmol/L), Vitamin B-12 is deficient.

Schilling test

If malabsorption is identified, the Schilling test can be repeated after a 2-week trial of an oral antibiotic. If antibiotic therapy corrects malabsorption, the likely cause is intestinal overgrowth of bacteria (eg, blind-loop syndrome).

Vitamin B12 deficiency treatment

Vitamin B12 deficiency can be treated with intramuscular injections of cyanocobalamin or hydroxocobalamin or oral vitamin B12 therapy. However, depending on the cause of the B12 deficiency, the duration and route of treatment vary. In patients who are B12 deficient due to a strict vegan diet, an oral supplement of B12 is adequate for repletion ³⁹. Vitamin B12 1000 to 2000 mcg (1 to 2 mg) orally can be given once/day to patients who do not have severe deficiency or neurologic symptoms or signs. A 2018 Cochrane review included three randomized controlled trials (RCTs) that compared very high doses (1,000–2,000 mcg) of oral with intramuscular vitamin B12 for vitamin B12 deficiency in a total of 153 participants ²³. The evidence from these studies, although of low quality, showed that the ability of high oral doses of vitamin B12 supplements to normalize serum vitamin B12 was similar to that of intramuscular vitamin B12. The British Society for Haematology recommends intramuscular vitamin B12 for severe deficiency and malabsorption syndromes, whereas oral replacement may be considered for patients with asymptomatic, mild disease with no absorption or compliance concerns ³⁸.

For more severe deficiency, vitamin B12 1 mg IM (intramuscularly) is usually given 1 to 4 times/week for several weeks until hematologic abnormalities are corrected; then it is given once/month. Approximately 10% of the standard injectable dose of 1 mg is absorbed, which allows for rapid replacement in patients with severe deficiency or severe neurologic sy mptoms ³³. Guidelines from the British Society for Haematology recommend injections three times per week for two weeks in patients without neurologic deficits ¹⁴³. If neurologic deficits are present, injections should be given every other day for up to three weeks or until no further improvement is noted. Table 4 lists the usual times until improvement for abnormalities associated with vitamin B12 deficiency ⁹. In general, patients with an irreversible cause should be treated indefinitely, whereas those with a reversible cause should be treated until the deficiency is corrected and symptoms resolve ¹². If vitamin B12 deficiency coexists with folate deficiency, vitamin B12 should be replaced first to prevent subacute combined degeneration of the spinal cord ¹². The British Society for Haematology does not recommend retesting vitamin B12 levels after treatment has been initiated, and no guidelines address the optimal interval for screening high-risk patients ¹⁴³.

Although hematologic abnormalities are usually corrected within 6 week (reticulocyte count should improve within 1 week), resolution of neurologic symptoms may take much longer. Neurologic symptoms that persist for months or years become irreversible. In most elderly people with vitamin B-12 deficiency and dementia, cognition does not improve after treatment.

There are 2 types of vitamin B12 injections:

Hydroxocobalamin
Cyanocobalamin

If vitamin B12 deficiency coexists with folate deficiency, vitamin B12 should be replaced first to prevent subacute combined degeneration of the spinal cord ¹².

Although hematologic abnormalities are usually corrected within 6 week (reticulocyte count should improve within 1 week), resolution of neurologic symptoms may take much longer. Neurologic symptoms that persist for months or years become irreversible. In most elderly people with Vitamin B-12 deficiency and dementia, cognition does not improve after treatment. Table 6 lists the usual times until improvement for abnormalities associated with vitamin B12 deficiency ⁹.

Vitamin B-12 treatment must be continued for life unless the pathophysiologic mechanism for the deficiency is corrected.

Infants of vegan mothers should receive supplemental Vitamin B-12 from birth.

In patients with a deficiency in intrinsic factor (IF), either due to pernicious anemia or gastric bypass surgery, a parenteral dose of vitamin B12 is recommended, as oral B12 will not be fully absorbed due to the lack of intrinsic factor. A dose of 1000 mcg of B12 via the intramuscular route is recommended once a month ²²⁹. In newly diagnosed patients, 1000 mcg of vitamin B12 is given intramuscularly once a week for four weeks to replenish stores before switching to once-monthly dosing ²²⁹. Studies have shown that at doses high enough to fully saturate intestinal B12 receptors, oral B12 is also effective, despite a lack of intrinsic factor ²²⁹.

In anyone at risk of developing a B12 deficiency, such as patients with Crohn’s disease or celiac disease, routine monitoring of B12 should be performed. If the severity of the disease worsens and B12 levels begin to decline, treatment is then started. However, prophylactic treatment before B12 levels fall is not indicated ²³⁷, ²³⁸, ²³⁹.

Table 6. Usual times until improvement for abnormalities associated with vitamin B12 deficiency

[Source ¹³ ]

Diet-related vitamin B12 deficiency

If your vitamin B12 deficiency is caused by a lack of the vitamin B12 in your diet, you may be advised to take vitamin B12 tablets every day between meals. Or you may need to have an vitamin B12 injection of hydroxocobalamin twice a year.

People who find it difficult to get enough vitamin B12 in their diets, such as those following a vegan diet, may need vitamin B12 tablets for life.

Although it’s less common, people with vitamin B12 deficiency caused by a prolonged poor diet may be advised to stop taking the tablets once their vitamin B12 levels have returned to normal and their diet has improved.

Good sources of vitamin B12 include:

meat
salmon and cod
milk and other dairy products
eggs

If you’re a vegetarian or vegan, or are looking for alternatives to meat and dairy products, there are other foods that contain vitamin B12, such as yeast extract (including Marmite), as well as some fortified breakfast cereals and soy products.

Check the nutrition labels while food shopping to see how much vitamin B12 different foods contain.

Non diet-related vitamin B12 deficiency

If your vitamin B12 deficiency is not caused by a lack of vitamin B12 in your diet, you’ll usually need to have an injection of hydroxocobalamin every 2 to 3 months for the rest of your life ²⁴⁰.

If you have had neurological symptoms that affect your nervous system, such as numbness or tingling in your hands and feet, caused by a vitamin B12 deficiency, you’ll be referred to a hematologist and may need to have vitamin B12 injections every 2 months. Your hematologist will advise on how long you need to keep taking the vitamin B12 injections.

For injections of vitamin B12 given in the UK, hydroxocobalamin is preferred to an alternative called cyanocobalamin ²⁴⁰. This is because hydroxocobalamin stays in the body for longer.

Monitoring your condition

It is essential for your healthcare provider to confirm vitamin B12 deficiency before starting therapy and a follow-up plan for the monitoring your response ²⁴¹. To ensure your treatment is working, you may need to have further blood tests. A blood test is often carried out around 7 to 10 days after starting treatment to assess whether treatment is working. If you have severe anemia associated with vitamin B12 deficiency, your blood response should lead to a marked increase in reticulocytes (precursors of red blood cells) by one-to-two weeks ²⁴¹. In mild vitamin B12 deficiency, this is less important, and follow-up should be done at two-to-three months after initiation of hydroxocobalamin ²⁴¹. These measurements should include vitamin B12 levels as well as homocysteine and methylmalonic acid (MMA) levels ²⁴². Both homocysteine and methylmalonic acid (MMA) are indicators for vitamin B12 levels and demonstrate your response to hydroxocobalamin ²⁴³. Most people who have had a vitamin B12 or folate deficiency will not need further monitoring unless their symptoms return or their treatment is ineffective ²⁴⁴.

Vitamin B12 deficiency prognosis

For patients who are promptly treated with vitamin B12, the prognosis is good. In general, younger patients have better outcomes compared to older individuals. The best response is obtained in people with the absence of severe neurological deficits. Therefore, it is important to start vitamin B12 treatment early. Nerve damage can be permanent if vitamin B12 treatment does not start within 6 months of symptoms. Although vitamin B12 supplementation stops progression and improves neurologic deficits in most patients with subacute combined degeneration, evidence shows complete resolution only occurs in a small percentage of them ¹⁷². A 2006 observational study evaluating 57 patients with subacute combined degeneration reported only 14% clinical resolution after B12 treatment ¹⁷². Still, the study reported that of these patients, 86% had at least some clinical improvement. Subgroup analysis revealed that the absence of sensory dermatomal deficit, negative Romberg and Babinski signs, age less than 50 years, and less than or equal to 7-segment involvement on magnetic resonance imaging correlated with complete resolution of neurologic symptoms ¹⁷². This study highlights the importance of early diagnosis and treatment of vitamin B12 deficiency, as patients with severe or prolonged neurological symptoms tend to have persistent symptoms despite treatment.

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Vitamin B12 deficiency

Vitamin B12 deficiency

Table 1. Risk factors for vitamin B12 deficiency

Table 2. Clinical and laboratory findings in vitamin B12 deficiency

Folic Acid and Vitamin B12 Deficiency

What is vitamin B12?

What does vitamin B12 do?

How much Vitamin B-12 do you need?

Table 3. Vitamin B-12 Recommended Intake

What are food sources of vitamin B12?

Table 4. Vitamin B12 Food Sources

Who are at risk of vitamin B12 deficiency?

Older adults

Individuals with pernicious anemia

Individuals with gastrointestinal disorders

Individuals who have had gastrointestinal surgery

Vegetarians

Infants of vegan women

What is pernicious anemia?

Pernicious anemia causes

Risk factors for pernicious anemia

Pernicious anemia prevention

Pernicious anemia signs and symptoms

General symptoms

Heart symptoms

Gastrointestinal symptoms

Neurologic symptoms

Genitourinary symptoms

Symptoms of thrombotic complications

Pernicious anemia complications

Pernicious anemia diagnosis

Testing for B12 Deficiency

Definitive Testing for Pernicious Anemia

Additional testing

Pernicious anemia treatment

Management Guidelines

Endoscopic Follow-Up

Pernicious anemia prognosis

Vitamin B12 deficiency causes

Atrophic gastritis

Pernicious anemia

Food-bound vitamin B12 malabsorption

Inherited disorders of vitamin B12 absorption

Other causes of vitamin B12 deficiency

Drug interactions

Groups at risk of vitamin B12 deficiency

Older adults

Individuals with pernicious anemia

Individuals with gastrointestinal disorders

Individuals who have had gastrointestinal surgery

Vegetarians

Infants of vegan women

Vitamin B12 deficiency prevention

Vitamin B12 deficiency signs and symptoms

Megaloblastic anemia

Neurologic symptoms

Gastrointestinal symptoms

Hyperhomocysteinemia

Vitamin B12 deficiency complications

Anemia complications

Neurological problems

Stomach cancer

Neural tube defects

Infertility

Effects of nitrous oxide

Vitamin B12 deficiency diagnosis

Vitamin B12 deficiency test

Schilling test

Vitamin B12 deficiency treatment

Diet-related vitamin B12 deficiency

Non diet-related vitamin B12 deficiency

Monitoring your condition

Vitamin B12 deficiency prognosis

The author Health Jade Team 3

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